Methods of treating cancer using pyridopyrimidinone inhibitors of p13k alpha

ABSTRACT

The present invention provides methods of treating cancer by administering a compound of Formula I, optionally as a pharmaceutically acceptable salt, solvate and/or hydrate thereof, in combination with other cancer treatments. 
     (Formula I)

CROSS-REFERENCE TO RELATED APPLICATIONS

The Applicants claim priority under 35 U.S.C. 119(e) to copendingProvisional Application No. 60/922,899 filed on Apr. 10, 2007, thedisclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to methods of treating cancer with a compoundthat inhibits lipid kinase enzymatic activity and the resultantmodulation of cellular activities (such as proliferation,differentiation, programmed cell death, migration, chemoinvasion andmetabolism) in combination with anticancer agents.

BACKGROUND OF THE INVENTION

Improvements in the specificity of agents used to treat various diseasestates such as cancer, metabolic, and inflammatory diseases is ofconsiderable interest because of the therapeutic benefits which would berealized if the side effects associated with the administration of theseagents could be reduced. Traditionally, dramatic improvements in thetreatment of cancer are associated with identification of therapeuticagents acting through novel mechanisms.

Phosphatidylinositol 3-kinase (PI3K or PIK3CA) is composed of an 85 kDaregulatory subunit and a 110 kDa catalytic subunit. The protein encodedby this gene represents the catalytic subunit, which uses ATP tophosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. PTEN, a tumorsuppressor which inhibits cell growth through multiple mechanisms, candephosphorylate PIP3, the major product of PIK3CA. PIP3, in turn, isrequired for translocation of protein kinase B (AKT1, PKB) to the cellmembrane, where it is phosphorylated and activated by upstream kinases.The effect of PTEN on cell death is mediated through the PIK3CA/AKT1pathway.

PI3Kα has been implicated in the control of cytoskeletal reorganization,apoptosis, vesicular trafficking, proliferation and differentiationprocesses. Increased copy number and expression of PIK3CA or activatingmutations in the p110a catalytic subunit of PIK3CA are associated with anumber of malignancies such as ovarian cancer (Campbell et al., CancerRes 2004, 64, 7678-7681; Levine et al., Clin Cancer Res 2005, 11,2875-2878; Wang et al., Hum Mutat 2005, 25, 322; Lee et al., GynecolOncol 2005, 97, 26-34), cervical cancer, breast cancer (Bachman, et al.Cancer Biol Ther 2004, 3, 772-775; Levine, et al., supra; Li et al.,Breast Cancer Res Treat 2006, 96, 91-95; Saal et al., Cancer Res 2005,65, 2554-2559; Samuels and Velculescu, Cell Cycle 2004, 3, 1221-1224),colorectal cancer (Samuels, et al. Science 2004, 304, 554; Velho et al.Eur J Cancer 2005, 41, 1649-1654), endometrial cancer (Oda et al. CancerRes. 2005, 65, 10669-10673), gastric carcinomas (Byun et al., Int JCancer 2003, 104, 318-327; Li et al., supra; Velho et al., supra; Lee etal., Oncogene 2005, 24, 1477-1480), hepatocellular carcinoma (Lee etal., id.), small and non-small cell lung cancer (Tang et al., LungCancer 2006, 51, 181-191; Massion et al., Am J Respir Crit Care Med2004, 170, 1088-1094), thyroid carcinoma (Wu et al., J Clin EndocrinolMetab 2005, 90, 4688-4693), acute myelogenous leukemia (AML) (Sujobertet al., Blood 1997, 106, 1063-1066), chronic myelogenous leukemia (CML)(Hickey and Cotter J Biol Chem 2006, 281, 2441-2450), and glioblastomas(Hartmann et al. Acta Neuropathol (Berl) 2005, 109, 639-642; Samuels etal., supra).

In view of the important role of PI3K-α in biological processes anddisease states, inhibitors and/or modulators of this lipid kinase aredesirable. In addition, it is well established that combining treatmentswith different mechanisms of action often leads to enhanced anti-tumoractivity as compared to single treatments administered alone. This istrue for combinations of chemotherapies (e.g. Kyrgiou M. et. al. J NatlCancer Inst 2006, 98, 1655) and combinations of antibodies andchemotherapy (e.g. Pasetto L M et. al. Anticancer Res 2006, 26, 3973.

For example, activation of the PI3K pathway contributes to theresistance of human tumor cells to a wide variety of chemotherapeuticagents, including microtubule stabilizing agents such as taxol(Brognard, J., et. al. Cancer Res 2001, 61, 3986-3997; Clark, A. S., et.al. Mol Cancer Ther 2002, 1, 707-717; Kraus, A. C., et. al. Oncogene2002, 21, 8683-8695; Krystal, G. W., et. al. Mol Cancer Ther 2002, 1,913-922; and Yuan, Z. Q., et. al. J Biol Chem 2003, 278, 23432-23440).Taxol is widely used to treat advanced cancers including prostatecarcinomas, which frequently harbor deletions in the PTEN gene,resulting in elevated signaling downstream of PI3K. A number ofpreclinical studies suggest that inhibiting signaling downstream of PI3Krestores or enhances the ability of chemotherapeutic agents such astaxol to kill tumor cells (Brognard, J., et. al. Cancer Res 2001, 61,3986-3997; Clark, A. S., et. al. Mol Cancer Ther 2002, 1, 707-717;Kraus, A. C., et. al. Oncogene 2002, 21, 8683-8695; Krystal, G. W., et.al. Mol Cancer Ther 2002, 1, 913-922; and Saga, Y., et. al. Clin CancerRes 2002, 8, 1248-1252).

Rapamycin, another chemotherapeutic agent, is a potent inhibitor of themTOR/Raptor complex. Inhibition of mTOR/Raptor prevents p70S6K and S6phosphorylation, but also leads to relief of a negative feedback loopemanating from p70S6K that serves to downregulate PI3K (Sarbassov, D.D., et. al. Science 2005, 307, 1098-1101). As a result, rapamycintreatment can lead to upregulation of PI3K and increased phosphorylationof AKT (O′Donnell, A., et. al. paper presented at Proc Am Soc ClinOncol. 2003; and O′Reilly, K. E., et. al. Cancer Res 2006, 66,1500-1508). Thus, combining rapamycin with inhibitors of PI3K canenhance the efficacy of rapamycin (Powis, G. et. al. Clinical CancerResearch 2006, 12, 2964-2966; Sun, S.-Y., et. al. Cancer Research 2005,65, 7052-7058).

A growing body of clinical and preclinical data indicates thatactivation of the PI3K pathway confers resistance to EGFR inhibitorssuch as erlotinib (Bianco, R., et. al. Oncogene 2003, 22, 2812-2822;Chakravarti, A., et. al. Cancer Res 2002, 62, 200-207; and Janmaat, M.L., et. al. Clin Cancer Res 2003, 9, 2316-2326). Both NSCLC patientswith K-Ras mutations and glioblastoma patients with PTEN deletions failto respond to erlotinib, potentially because of genetic activation ofthe PI3K pathway (Mellinghoff, I. K., et. al. N. Eng. J Med. 2006, 353,2012-2024). Preclinical studies have shown that downregulation of PI3Ksignaling in EGFR-expressing tumor cells confers increased sensitivityto EGFR inhibitors (Ihle, N. T., et. al. Mol Cancer Ther 2005, 4,1349-1357). Thus, treating cancer with a PI3K inhibitor in combinationwith an EGFR inhibitor, such as erlotinib, is desirable.

Activation of the PI3K pathway also contributes to the resistance ofhuman tumor cells to DNA damaging agents, such as platins. A number ofpreclinical studies suggest that inhibiting signaling downstream of PI3Krestores or enhances the ability of chemotherapeutic agents such asplatins to kill tumor cells (Brognard, J., et. al. Cancer Res 2001, 61,3986-3997; and Yuan, Z. Q., et. al. J Biol Chem 2003, 278, 23432-23440).Carboplatin is widely used to treat advanced cancers including non-smallcell lung carcinomas (NSCLC), which frequently harbor activatingmutations in the K-Ras gene, resulting in activation of PI3K(Aviel-Ronen S., et. al. Clin Lung Cancer 2006, 8, 30-38). NSCLCpatients with K-Ras mutations do not respond to EGFR inhibitors such asTarceva, and thus represent a significant unmet medical need (Janne P A,et. al. J Clin Oncology 2005, 23, 3227-3234). Thus, treating NSCLC witha DNA-damaging agent such as a platin in combination with an inhibitorof PI3K is desirable in light of the lack of efficacious treatments.

Treatments that combine an inhibitor of PI3K-α with other anti-canceragents are desirable and needed.

SUMMARY OF THE INVENTION

The following only summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below. All references cited inthis specification are hereby incorporated by reference in theirentirety. In the event of a discrepancy between the express disclosureof this specification and the references incorporated by reference, theexpress disclosure of this specification shall control.

The compositions of the invention are used to treat diseases associatedwith abnormal and or unregulated cellular activities. Disease stateswhich can be treated by the methods and compositions provided hereininclude cancer. The invention is directed to methods of treating thesediseases by administering a Compound of Formula I or II in combinationwith one or more treatments.

One aspect of the Invention is directed to a method of treating cancerwhich method comprises administering to a patient a therapeuticallyeffective amount of a Compound of Formula I:

or a single isomer thereof where the compound is optionally as apharmaceutically acceptable salt and additionally optionally as ahydrate and additionally optionally as a solvate thereof; oradministering a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula I and a pharmaceuticallyacceptable carrier, excipient, or diluent in combination with one ormore treatments independently selected from surgery, one or morechemotherapeutic agents, one or more hormone therapies, one or moreantibodies, one or more immunotherapies, radioactive iodine therapy, andradiation, where the Compound of Formula I is that wherein:

-   R¹ is hydrogen, optionally substituted alkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heterocycloalkyl, optionally substituted    heterocycloalkylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   R² is hydrogen or alkyl where the alkyl is optionally substituted    with 1, 2, 3, 4, or 5 R⁸ groups;-   X is —NR³—;-   R³ hydrogen;-   R⁴ is optionally substituted alkyl;-   R⁵ is hydrogen; and-   R⁶ is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl    are optionally substituted with 1, 2, 3, 4, or 5 R⁹ groups;-   each R⁸, when present, is independently hydroxy, halo, alkoxy,    haloalkoxy, amino, alkylamino, dialkylaminoalkyl, or    alkoxyalkylamino; and-   each R⁹, when present, is independently halo, alkyl, haloalkyl,    alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino,    alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, aminoalkyl, cycloalkyl,    aryl, arylalkyl, aryloxy, heterocycloalkyl, or heteroaryl and where    the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each either    alone or as part of another group within R⁹, are independently    optionally substituted with 1, 2, 3, or 4 groups selected from halo,    alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino,    and dialkylamino.

A second aspect of the Invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula II:

or a single isomer thereof where the compound is optionally as apharmaceutically acceptable salt and additionally optionally as ahydrate and additionally optionally as a solvate thereof; oradministering a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula II and a pharmaceuticallyacceptable carrier, excipient, or diluent in combination with one ormore treatments independently selected from surgery, one or morechemotherapeutic agents, one or more hormone therapies, one or moreantibodies, one or more immunotherapies, radioactive iodine therapy, andradiation, where the Compound of Formula II is that wherein:

-   R¹ is hydrogen, optionally substituted alkyl, optionally substituted    C₃-C₇ cycloalkyl, optionally substituted aryl, optionally    substituted arylalkyl, optionally substituted heterocycloalkyl,    optionally substituted heterocycloalkylalkyl, optionally substituted    heteroaryl or optionally substituted heteroarylalkyl;-   X is S, SO₂, or —NR³—;-   R² is hydrogen, haloalkyl, optionally substituted alkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl,    optionally substituted arylalkyl, optionally substituted    heterocycloalkyl, optionally substituted heterocycloalkylalkyl,    optionally substituted heterocycloalkyl-aryl- or optionally    substituted heteroaryl; R² is optionally further substituted with    one or more R⁸ groups;-   R³, R^(3a), and R^(3b) are independently hydrogen, optionally    substituted alkyl, optionally substituted C₃-C₇ cycloalkyl,    optionally substituted aryl, optionally substituted heterocycloalkyl    or optionally substituted heteroaryl;-   R⁴ is hydrogen, halo, haloalkyl, haloalkoxy, —NR^(3a)—, optionally    substituted alkyl, optionally substituted C₁-C₆ alkoxy, optionally    substituted C₁-C₆ alkoxyalkyl, optionally substituted aminoalkyl,    optionally substituted C₃-C₇ cycloalkyl, optionally substituted    aryl, or optionally substituted heteroaryl;-   R⁵ is hydrogen, halo, haloalkyl, haloalkoxy, optionally substituted    C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, optionally    substituted C₁-C₆ alkoxyalkyl, optionally substituted aminoalkyl,    optionally substituted C₃-C₇ cycloalkyl, optionally substituted    aryl, optionally substituted aryl C₁-C₆ alkyl or optionally    substituted heteroaryl; and-   R⁶ is hydrogen, halo, haloalkyl, haloalkoxy, —NR^(3b)—, optionally    substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy,    optionally substituted C₁-C₆ alkoxyalkyl, optionally substituted    acyl, optionally substituted aminoalkyl, optionally substituted    C₃-C₇ cycloalkyl, optionally substituted aryl, optionally    substituted arylalkyl, optionally substituted heterocycloalkyl, or    optionally substituted heteroaryl; substitutable R⁶ groups are    optionally further substituted with 1, 2, 3, 4, or 5 R⁹ groups;-   each R⁸, when present, is independently hydroxy, halo, haloalkyl,    haloalkoxy, optionally substituted alkyl, optionally substituted    C₁-C₆ alkoxy, optionally substituted C₁-C₆ alkoxyalkyl, optionally    substituted C₁-C₆ alkoxyalkylaminoalkyl, C₁-C₆    alkylcarboxyheterocycloalkyl, oxy C₁-C₆alkylheterocycloalkyl,    optionally substituted aminoalkyl, optionally substituted C₃-C₇    cycloalkyl, optionally substituted aryl, optionally substituted aryl    C₁-C₆ alkyl, optionally substituted heterocycloalkyl, optionally    substituted heterocycloalkylalkyl, optionally substituted heteroaryl    or optionally substituted heteroarylalkyl;-   each R⁹, when present, is independently halo, haloalkyl, haloalkoxy,    optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆    alkoxy, optionally substituted C₁-C₆ alkoxyalkyl, optionally    substituted C₁-C₆ carboxyalkyl, optionally substituted    alkoxycarbonyl, optionally substituted aminoalkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl,    optionally substituted aryl C₁-C₆ alkyl, optionally substituted    aryloxy, optionally substituted heterocycloalkyl, or optionally    substituted heteroaryl.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning Ac acetyl br broad ° C. degrees Celsius c- cycloCBZ CarboBenZoxy = benzyloxycarbonyl d doublet dd doublet of doublet dtdoublet of triplet DCM dichloromethane DME 1,2-dimethoxyethane DMFN,N-dimethylformamide DMSO dimethyl sulfoxide dppf1,1′-bis(diphenylphosphano)ferrocene EI Electron Impact ionization ggram(s) h or hr hour(s) HPLC high pressure liquid chromatography Lliter(s) M molar or molarity m Multiplet mg milligram(s) MHz megahertz(frequency) Min minute(s) mL milliliter(s) μL microliter(s) μMMicromole(s) or micromolar mM Millimolar mmol millimole(s) mol mole(s)MS mass spectral analysis N normal or normality nM Nanomolar NMR nuclearmagnetic resonance spectroscopy q Quartet RT Room temperature s Singlett or tr Triplet TFA trifluoroacetic acid THF tetrahydrofuran TLC thinlayer chromatography

DEFINITIONS FOR A COMPOUND OF FORMULA I AND II

The symbol “

” means a single bond, “

” means a double bond, “

” means a triple bond, “

” means a single or double bond. The symbol “

” refers to a group on a double-bond as occupying either position on theterminus of a double bond to which the symbol is attached; that is, thegeometry, E- or Z-, of the double bond is ambiguous. When a group isdepicted removed from its parent formula, the “

” symbol will be used at the end of the bond which was theoreticallycleaved in order to separate the group from its parent structuralformula.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted hydrogen(for example the —NH— in the formula above), implied hydrogen (forexample as in the formula above, where the hydrogens are not shown butunderstood to be present), or expressly defined hydrogen (for examplewhere in the formula above, “Z” equals ═CH—) from one of the ring atoms,so long as a stable structure is formed. In the example depicted, the“R” group may reside on either the 5-membered or the 6-membered ring ofthe fused ring system. In the formula depicted above, when y is 2 forexample, then the two “R's” may reside on any two atoms of the ringsystem, again assuming each replaces a depicted, implied, or expresslydefined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Acyl” means a —C(O)R radical where R is optionally substituted alkyl,optionally substituted alkenyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, orheterocycloalkylalkyl, as defined herein, e.g., acetyl,trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and the like.

“Acylamino” means a —NRR′ radical where R is hydrogen, hydroxy, alkyl,or alkoxy and R′ is acyl, as defined herein.

“Acyloxy” means an —OR radical where R is acyl, as defined herein, e.g.cyanomethylcarbonyloxy, and the like.

“Administration” and variants thereof (e.g., “administering” a compound)in reference to a compound of the invention means introducing thecompound or a prodrug of the compound into the system of the animal inneed of treatment. When a compound of the invention or prodrug thereofis provided in combination with one or more other active agents (e.g.,surgery, radiation, and chemotherapy, etc.), “administration” and itsvariants are each understood to include concurrent and sequentialintroduction of the compound or prodrug thereof and other agents.

“Alkenyl” means a means a linear monovalent hydrocarbon radical of oneto six carbon atoms or a branched monovalent hydrocarbon radical ofthree to 6 carbon atoms which radical contains at least one double bond,e.g., ethenyl, propenyl, 1-but-3-enyl, and 1-pent-3-enyl, and the like.

“Alkoxy” means an —OR group where R is alkyl group as defined herein.Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

“Alkoxyalkyl” means an alkyl group, as defined herein, substituted withat least one, preferably one, two, or three, alkoxy groups as definedherein. Representative examples include methoxymethyl and the like.

“Alkoxyalkylamino” means an NRR′ group where R is hydrogen, alkyl, oralkoxyalkyl and R′ is alkoxyalkyl, as defined herein.

“Alkoxyalkylaminoalkyl” means an alkyl group substituted with at leastone, specifically one or two, alkoxyalkylamino groups, as definedherein.

“Alkoxycarbonyl” means a —C(O)R group where R is alkoxy, as definedherein.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to 6 carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), or pentyl (including allisomeric forms), and the like.

“Alkylamino” means an —NHR group where R is alkyl, as defined herein.

“Alkylaminoalkyl” means an alkyl group substituted with one or twoalkylamino groups, as defined herein.

“Alkylaminoalkyloxy” means an —OR group where R is alkylaminoalkyl, asdefined herein.

“Alkylcarbonyl” means a —C(O)R group where R is alkyl, as definedherein.

“Alkynyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three to 6carbon atoms which radical contains at least one triple bond, e.g.,ethynyl, propynyl, butynyl, pentyN-2-yl and the like.

“Amino” means —NH₂.

“Aminoalkyl” means an alkyl group substituted with at least one, forexample one, two or three, amino groups.

“Aminoalkyloxy” means an —OR group where R is aminoalkyl, as definedherein.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Unless statedotherwise, the valency of the group may be located on any atom of anyring within the radical, valency rules permitting. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Arylalkyl” means an alkyl radical, as defined herein, substituted withone or two aryl groups, as defined herein, e.g., benzyl and phenethyl,and the like.

“Aryloxy” means an —OR group where R is aryl, as defined herein.

“Carboxyalkyl” means an alkyl group, as defined herein, substituted withat least one, for example one or two, —C(O)OH groups.

“Cycloalkyl” means a monocyclic or fused bicyclic, saturated orpartially unsaturated (but not aromatic), monovalent hydrocarbon radicalof three to ten carbon ring atoms. Fused bicyclic hydrocarbon radicalincludes bridged ring systems. Unless stated otherwise, the valency ofthe group may be located on any atom of any ring within the radical,valency rules permitting. One or two ring carbon atoms may be replacedby a —C(O)—, —C(S)—, or —C(═NH)— group. In another embodiment, the termcycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3-enyl, and the like.

“Cycloalkylalkyl” means an alkyl group substituted with at least one,for example one or two, cycloalkyl groups as defined herein.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as definedherein, or an N-oxide derivative, or a protected derivative thereof,e.g., dimethylamino, diethylamino, N,N-methylpropylamino orN,N-methylethylamino, and the like.

“Dialkylaminoalkyl” means an alkyl group substituted with one or twodialkylamino groups, as defined herein.

“Dialkylaminoalkyloxy” means an —OR group where R is dialkylaminoalkyl,as defined herein. Representative examples include2-(N,N-diethylamino)-ethyloxy, and the like.

“Fused-polycyclic” or “fused ring system” means a polycyclic ring systemthat contains bridged or fused rings; that is, where two rings have morethan one shared atom in their ring structures. In this application,fused-polycyclics and fused ring systems are not necessarily allaromatic ring systems. Typically, but not necessarily, fused-polycyclicsshare a vicinal set of atoms, for example naphthalene or1,2,3,4-tetrahydro-naphthalene. A Spiro ring system is not afused-polycyclic by this definition, but fused polycyclic ring systemsof the invention may themselves have spiro rings attached thereto via asingle ring atom of the fused-polycyclic. In some examples, asappreciated by one of ordinary skill in the art, two adjacent groups onan aromatic system may be fused together to form a ring structure. Thefused ring structure may contain heteroatoms and may be optionallysubstituted with one or more groups. It should additionally be notedthat saturated carbons of such fused groups (i.e. saturated ringstructures) can contain two substitution groups.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

“Haloalkoxy” means an —OR′ group where R′ is haloalkyl as definedherein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

“Haloalkyl” mean an alkyl group substituted with one or more halogens,for example one to five halo atoms, e.g., trifluoromethyl,2-chloroethyl, and 2,2-difluoroethyl, and the like.

“Heteroaryl” means a monocyclic, fused bicyclic, or fused tricyclic,monovalent radical of 5 to 14 ring atoms containing one or more, forexample one, two, three, or four ring heteroatoms independently selectedfrom —O—, —S(O)_(N-) (n is 0, 1, or 2), —N—, —N(R^(x))—, and theremaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic. One or tworing carbon atoms of any nonaromatic rings comprising a bicyclic ortricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)—group. R^(x) is hydrogen, alkyl, hydroxy, alkoxy, acyl, oralkylsulfonyl. Fused bicyclic radical includes bridged ring systems.Unless stated otherwise, the valency may be located on any atom of anyring of the heteroaryl group, valency rules permitting. When the pointof valency is located on the nitrogen, R^(x) is absent. In anotherembodiment, the term heteroaryl includes, but is not limited to,1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl,imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl(including, for example, 2,3-dihydro-1H-indol-2-yl or2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, indolinyl,isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl,cinnolinyl, indolizinyl, naphthyridiN-3-yl, phthalaziN-3-yl,phthalaziN-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl,tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl (including, for example,tetrahydroisoquinoliN-4-yl or tetrahydroisoquinoliN-6-yl, and the like),pyrrolo[3,2-c]pyridinyl (including, for example,pyrrolo[3,2-c]pyridiN-2-yl or pyrrolo[3,2-c]pyridiN-7-yl, and the like),benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl,benzothienyl, and the derivatives thereof, or N-oxide or a protectedderivative thereof.

“Heteroarylalkyl” means an alkyl group, as defined herein, substitutedwith at least one, for example one or two heteroaryl groups, as definedherein.

“Heteroatom” refers to O, S, N, or P.

“Heterocycloalkyl” means a saturated or partially unsaturated (but notaromatic) monovalent monocyclic group of 3 to 8 ring atoms or asaturated or partially unsaturated (but not aromatic) monovalent fusedbicyclic group of 5 to 12 ring atoms in which one or more, for exampleone, two, three, or four ring heteroatoms independently selected from O,S(O)_(n) (n is 0, 1, or 2), N,N(R^(y)) (where R^(y) is hydrogen, alkyl,hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms beingcarbon. One or two ring carbon atoms may be replaced by a —C(O)—,—C(S)—, or —C(═NH)— group. Fused bicyclic radical includes bridged ringsystems. Unless otherwise stated, the valency of the group may belocated on any atom of any ring within the radical, valency rulespermitting. When the point of valency is located on a nitrogen atom,R^(y) is absent. In another embodiment the term heterocycloalkylincludes, but is not limited to, azetidinyl, pyrrolidinyl,2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl,morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl,2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl,tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl,thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl,octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl,tetrahydrofuryl, and tetrahydropyranyl, and the derivatives thereof andN-oxide or a protected derivative thereof.

“Heterocycloalkylalkyl” means an alkyl radical, as defined herein,substituted with one or two heterocycloalkyl groups, as defined herein,e.g., morpholinylmethyl, N-pyrrolidinylethyl, and3-(N-azetidinyl)propyl, and the like.

“Heterocycloalkylalkyloxy means an —OR group where R isheterocycloalkylalkyl, as defined herein.

“Saturated bridged ring system” refers to a bicyclic or polycyclic ringsystem that is not aromatic. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon). Forexample, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene,7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthaleneare all included in the class “saturated bridged ring system.

“Spirocyclyl” or “spirocyclic ring” refers to a ring originating from aparticular annular carbon of another ring. For example, as depictedbelow, a ring atom of a saturated bridged ring system (rings B and B′),but not a bridgehead atom, can be a shared atom between the saturatedbridged ring system and a spirocyclyl (ring A) attached thereto. Aspirocyclyl can be carbocyclic or heteroalicyclic.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that withrespect to any molecule described as containing one or more optionalsubstituents, only sterically practical and/or synthetically feasiblecompounds are meant to be included. “Optionally substituted” refers toall subsequent modifiers in a term. So, for example, in the term“optionally substituted arylC₁₋₈alkyl,” optional substitution may occuron both the “C₁₋₈ alkyl” portion and the “aryl” portion of the moleculemay or may not be substituted. A list of exemplary optionalsubstitutions is presented below in the definition of “substituted.”

“Optionally substituted alkoxy” means an —OR group where R is optionallysubstituted alkyl, as defined herein.

“Optionally substituted alkyl” means an alkyl radical, as definedherein, optionally substituted with one or more groups, for example one,two, three, four, or five groups, independently selected fromalkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cyano,cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy,halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)₀₋₂—,alkenyl-S(O)₀₋₂—, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl-NR^(c)— (where R^(c) is hydrogen,alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, orcyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl,alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino,dialkylaminocarbonylamino, alkoxyalkyloxy, and —C(O)NR^(a)R^(b) (whereR^(a) and R^(b) are independently hydrogen, alkyl, optionallysubstituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).

“Optionally substituted alkenyl” means an alkyl radical, as definedherein, optionally substituted with one or more groups, for example one,two, three, four, or five groups, independently selected fromalkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cyano,cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy,halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)₀₋₂—,alkenyl-S(O)₀₋₂—, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl-NR^(c)— (where R^(c) is hydrogen,alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, orcyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl,alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino,dialkylaminocarbonylamino, alkoxyalkyloxy, and —C(O)NR^(a)R^(b) (whereR^(a) and R^(b) are independently hydrogen, alkyl, optionallysubstituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).

“Optionally substituted amino” refers to the group —N(H)R or —N(R)Rwhere each R is independently selected from the group: optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedaryl, optionally substituted heterocycloalkyl, optionally substitutedheteroaryl, acyl, carboxy, alkoxycarbonyl, —S(O)₂-(optionallysubstituted alkyl), —S(O)₂-optionally substituted aryl),—S(O)₂-(optionally substituted heterocycloalkyl), —S(O)₂-(optionallysubstituted heteroaryl), and —S(O)₂-(optionally substituted heteroaryl).For example, “optionally substituted amino” includes diethylamino,methylsulfonylamino, and furanyl-oxy-sulfonamino.

“Optionally substituted aminoalkyl” means an alkyl group, as definedherein, substituted with at least one, for example one or two,optionally substituted amino groups, as defined herein.

“Optionally substituted aryl” means an aryl group, as defined herein,optionally substituted with one, two, or three substituentsindependently selected from acyl, acylamino, acyloxy, optionallysubstituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy,halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino,dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Withinthe optional substituents on “aryl”, the alkyl and alkenyl, either aloneor as part of another group (including, for example, the alkyl inalkoxycarbonyl), are independently optionally substituted with one, two,three, four, or five halo.

“Optionally substituted arylalkyl” means an alkyl group, as definedherein, substituted with optionally substituted aryl, as defined herein.

“Optionally substituted cycloalkyl” means a cycloalkyl group, as definedherein, substituted with one, two, or three groups independentlyselected from acyl, acyloxy, acylamino, optionally substituted alkyl,optionally substituted alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl,alkenyloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro,alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy,carboxy, and cyano. Within the above optional substitutents on“cycloalkyl”, the alkyl and alkenyl either alone or as part of anothersubstituent on the cycloalkyl ring, are independently optionallysubstituted with one, two, three, four, or five halo, e.g. haloalkyl,haloalkoxy, haloalkenyloxy, or haloalkylsulfonyl.

“Optionally substituted cycloalkylalkyl” means an alkyl groupsubstituted with at least one, for example one or two, optionallysubstituted cycloalkyl groups, as defined herein.

“Optionally substituted heteroaryl” means a heteroaryl group optionallysubstituted with one, two, or three substituents independently selectedfrom acyl, acylamino, acyloxy, optionally substituted alkyl, optionallysubstituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl,alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano,alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino,aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy. Within theoptional substituents on “heteroaryl”, the alkyl and alkenyl, eitheralone or as part of another group (including, for example, the alkyl inalkoxycarbonyl), are independently optionally substituted with one, two,three, four, or five halo.

“Optionally substituted heteroarylalkyl” means an alkyl group, asdefined herein, substituted with at least one, for example one or two,optionally substituted heteroaryl groups, as defined herein.

“Optionally substituted heterocycloalkyl” means a heterocycloalkylgroup, as defined herein, optionally substituted with one, two, or threesubstituents independently selected from acyl, acylamino, acyloxy,optionally substituted alkyl, optionally substituted alkenyl, alkoxy,alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino,alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Withinthe optional substituents on “heterocycloalkyl”, the alkyl and alkenyl,either alone or as part of another group (including, for example, thealkyl in alkoxycarbonyl), are independently optionally substituted withone, two, three, four, or five halo.

“Optionally substituted heterocycloalkylalkyl” means an alkyl group, asdefined herein, substituted with at least one, for example one or two,optionally substituted heterocycloalkyl groups as defined herein.

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

DEFINITIONS FOR THE COMPOUND OF FORMULA 100

The terms used to describe the scope of formula 100 are defined in WO2004/006846 (US Nat'l Stage application Ser. No. 10/522,004) which isherein incorporated by reference. For example “optionally substitutedalkyl” for formula 100 has the meaning given in WO 2004/006846 (US Nat'lStage application Ser. No. 10/522,004). Whenever a compound of formula100 is described in this application, whether by structure or by use ofthe term “formula 100,” the terms used to describe that compound aredefined by WO 2004/006846 (US Nat'l Stage application Ser. No.10/522,004).

OTHER DEFINITIONS

“AKT inhibitor” includes, for example, LY294002, PKC 412, perifosine,compounds in Table 2a, compounds in Table 2b, and compounds described inWO 2006/071819 and WO05/117909. These references also describe in vitroassays that can be used to determine the inhibitory activity of AKT.

“Alkylating agent” includes, for example, one or more of the following:Chlorambucil, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan,Carmustine, Streptozocin, Fotemustine, Lomustine, Streptozocin,Carboplatin, Cisplatin, Oxaliplatin, BBR3464, Busulfan, Dacarbazine,Mechlorethamine, Procarbazine, Temozolomide, ThioTEPA, and Uramustine.

“Antibody” includes, for example, one or more of the following: an IGF1Rantibody (including, for example, ^(α)IGF-1R A12 MoAb, 19D12, h7C10 andCP-751871), an EGFR antibody (including, for example, Cetuximab(Erbitux®) and Panitumumab), an ErbB2 antibody (including, for example,Trastuzumab (Herceptin®)), a VEGF antibody (including, for example,Bevacizumab (Avastin®)), an IgG1 antibody (including, for example,Ibritumomab (tiuxetan)), a CD20 antibody (including, for example,Rituximab and Tositumomab), a CD33 antibody (including, for example,Gemtuzumab and Gemtuzumab ozogamicin), and a CD52 antibody (including,for example, Alemtuzumab).

“Antimetabolite” includes, for example, methotrexate, Pemetrexed,Raltitrexed, Cladribine, Clofarabine, Fludarabine, Mercaptopurine,Thioguanine, Capecitabine, Cytarabine, fluorouracil (administered withor without leucovorin or folinic acid), and Gemcitabine.

“Antimicrotubule agent” includes, for example, Vincristine, Vinblastine,Vinorelbine, Vinflunine, and Vindesine.

“Aromatase inhibitor” includes, for example, one or more of thefollowing: Aminoglutethimide, Anastrozole (Arimidex®), Letrozole(Femara®), Exemestane (Aromasin®), and Formestane (Lentaron®).

“Cancer” refers to cellular-proliferative disease states, including butnot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis defornians), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;Adrenal Glands: neuroblastoma; and breast cancer. Thus, the term“cancerous cell” as provided herein, includes a cell afflicted by anyone of the above-identified conditions.

“Chemotherapeutic agent” includes, but is not limited to, an AKTinhibitor, an alkylating agent, an antimetabolite, an antimicrotubuleagent, an aromatase inhibitor, a c-KIT inhibitor, a cMET inhibitor, anEGFR inhibitor, an ErbB2 inhibitor, a Flt-3 inhibitor, an HSP90inhibitor, an IGF1R inhibitor, a platin, a Raf inhibitor, rapamycin, aRapamycin analogue, a Receptor Tyrosine Kinase inhibitor, a taxane, atopoisomerase inhibitor, a SRC and/or ABL kinase inhibitor, and a VEGFRinhibitor. A pharmaceutically acceptable salt, solvate, and/or hydrateof a chemotherapeutic agent can be prepared by one of ordinary skill inthe art and such salt, solvate, and/or hydrates thereof can be used topractice the invention.

“c-KIT inhibitor” includes, for example, imatinib, sunitinib, nilotinib,AMG 706, sorafenib, compounds in Table 3b, compounds in Table 3c,compounds in Table 8, compounds in Table 9, and compounds described inWO 2006/108059, WO/2005/020921, WO/2006/033943, and WO 2005/030140.

“cMET inhibitor” includes, for example, compounds in Table 3a, compoundsin Table 3b, compounds in Table 3c, compounds described in WO06/108059,WO 2006/014325, and WO 2005/030140.

“EGFR inhibitor”includes, for example, one or more of the following:pelitinib, lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib(Tarceva®), Zactima (ZD6474, vandetinib), AEE788 and HKI-272, EKB-569,CI-1033,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,compounds in Table 4, compounds in Table 7, and compounds described inWO 2004/006846 and WO 2004/050681.

“ErbB2 inhibitor” includes, for example, lapatinib (GW572016), PKI-166,canertinib, CI-1033, HKI272, and EKB-569.

“Flt-3 inhibitor” includes, for example, CEP-701, PKC 412, MLN 518,sunitinib, sorafenib, compounds in Table 3a, compounds in Table 3b,compounds in Table 3c, compounds in Table 9, and compounds described inWO 2006/108059, WO/2006/033943, WO 2006/014325, and WO 2005/030140.

“Hormone therapy” and “hormonal therapy” include, for example, treatmentwith one or more of the following: steroids (e.g. dexamethasone),finasteride, tamoxifen, and an aromatase inhibitor.

“HSP90 inhibitor” includes, for example, 17-AAG, 17-DMAG, Geldanamycin,5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide[NVP-AUY922 (VER 52296)],6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-2-amine(CNF2024, also named BIIB021), compounds disclosed in WO2004072051(which is herein incorporated by reference), compounds disclosed inWO2005028434 (which is herein incorporated by reference), compoundsdisclosed in WO2007035620 (which is herein incorporated by reference)and compounds disclosed in WO2006091963 (which is herein incorporated byreference).

“IGF1R inhibitor” includes, for example, Tyrphostin AG 1024, compoundsin Table 5a, compounds in Table 5b, and compounds described inWO06/074057.

“Kinase-dependent diseases or conditions” refer to pathologic conditionsthat depend on the activity of one or more protein kinases. Kinaseseither directly or indirectly participate in the signal transductionpathways of a variety of cellular activities including proliferation,adhesion, migration, differentiation and invasion. Diseases associatedwith kinase activities include tumor growth, the pathologicneovascularization that supports solid tumor growth, and associated withother diseases where excessive local vascularization is involved such asocular diseases (diabetic retinopathy, age-related macular degeneration,and the like) and inflammation (psoriasis, rheumatoid arthritis, and thelike).

While not wishing to be bound to theory, phosphatases can also play arole in “kinase-dependent diseases or conditions” as cognates ofkinases; that is, kinases phosphorylate and phosphatasesdephosphorylate, for example protein substrates. Therefore compounds ofthe invention, while modulating kinase activity as described herein, mayalso modulate, either directly or indirectly, phosphatase activity. Thisadditional modulation, if present, may be synergistic (or not) toactivity of compounds of the invention toward a related or otherwiseinterdependent kinase or kinase family. In any case, as statedpreviously, the compounds of the invention are useful for treatingdiseases characterized in part by abnormal levels of cell proliferation(i.e. tumor growth), programmed cell death (apoptosis), cell migrationand invasion and angiogenesis associated with tumor growth.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.thEd., Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be used such thatthe biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In a preferred embodiment the patient is a mammal, and ina most preferred embodiment the patient is human.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference orS. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 both of which are incorporated herein by reference.

Examples of pharmaceutically acceptable acid addition salts includethose formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; as wellas organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid and the like.

Examples of a pharmaceutically acceptable base addition salts includethose formed when an acidic proton present in the parent compound isreplaced by a metal ion, such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Preferable salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins. Examples of organic bases include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

“Platin,” and “platin-containing agent” include, for example, cisplatin,carboplatin, and oxaliplatin.

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)the alkyl group is a straight or branched chain. Acceptable esters alsoinclude cycloalkyl esters and arylalkyl esters such as, but not limitedto benzyl. Examples of pharmaceutically acceptable amides of thecompounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Raf inhibitor” includes, for example, sorafenib, RAF 265 (CHIR 265),compounds in Table 6, and compounds described in WO 2005/112932. Thesereferences also describe in vitro assays that can be used to determinethe inhibitory activity of RAF.

“Rapamycin analogue” includes for example, CCI-779, AP 23573, RAD 001,TAFA 93, and compounds described in WO 2004/101583 and U.S. Pat. No.7,160,867 which are each incorporated herein by reference in theirentireties.

“Receptor Tyrosine Kinase inhibitor” includes, for example, inhibitorsof AKT, EGFR, ErbB2, IGF1R, KIT, Met, Raf, and VEGFR2. Examples ofreceptor tyrosine kinase inhibitors can be found in WO 2006/108059 (USNat'l Stage application Ser. No. 11/910,720), WO 2006/074057 (US Nat'lStage application Ser. No. 11/722,719), WO 2006/071819 (US Nat'l Stageapplication Ser. No. 11/722,291), WO 2006/014325 (US Nat'l Stageapplication Ser. No. 11/571,140), WO 2005/117909 (US Nat'l Stageapplication Ser. No. 11/568,173), WO 2005/030140 (US Nat'l Stageapplication Ser. No. 10/573,336), WO 2004/050681 US Nat'l Stageapplication Ser. No. 10/533,555), WO 2005/112932 (US Nat'l Stageapplication Ser. No. 11/568,789), and WO 2004/006846 (US Nat'l Stageapplication Ser. No. 10/522,004), each of which is incorporated hereinby reference for all purposes. In particular, the applications cited inthis paragraph are incorporated for the purpose of providing specificexamples and generic embodiments (and the definitions associated withthe terms used in the embodiments) of compounds that are useful in thepractice of the invention. These references also describe in vitroassays useful in the practice of this invention.

“Taxane” includes, for example, one or more of the following: Paclitaxel(Taxol®) and Docetaxel (Taxotere®).

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto their knowledge and to this disclosure.

“Topoisomerase inhibitor” includes, for example, one or more of thefollowing: amsacrine, camptothecin, etoposide, etoposide phosphate,exatecan, irinotecan, lurtotecan, and teniposide, and topotecan.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) preventing the disease, disorder, or syndrome fromoccurring in a human, i.e. causing the clinical symptoms of the disease,disorder, or syndrome not to develop in an animal that may be exposed toor predisposed to the disease, disorder, or syndrome but does not yetexperience or display symptoms of the disease, disorder, or syndrome;(ii) inhibiting the disease, disorder, or syndrome, i.e., arresting itsdevelopment; and (iii) relieving the disease, disorder, or syndrome,i.e., causing regression of the disease, disorder, or syndrome. As isknown in the art, adjustments for systemic versus localized delivery,age, body weight, general health, sex, diet, time of administration,drug interaction and the severity of the condition may be necessary, andwill be ascertainable with routine experimentation by one of ordinaryskill in the art.

“SRC and/or ABL kinase inhibitor” includes, for example, dasatinib,imatinib (Gleevec®), and compounds described in WO 2006/074057.

“VEGFR inhibitor” includes, for example, one or more of the following:VEGF

Trap, ZD6474 (vandetanib, Zactima), sorafenib, Angiozyme, AZD2171(cediranib), pazopanib, sorafenib, axitinib, SU5416 (semaxanib), PTK787(vatalanib), AEE778, RAF 265, sunitinib (Sutent),N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,compounds in Table 7, and compounds described in WO 2004/050681 and WO2004/006846.

Embodiments of the Invention

The following paragraphs present a number of embodiments of compoundsthat can be used to practice the invention. In each instance, theembodiment includes both the recited compounds as well as individualisomers and mixtures of isomers. In addition, in each instance, theembodiment includes the pharmaceutically acceptable salts, hydrates,and/or solvates of the recited compounds and any individual isomers ormixture of isomers thereof.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, where growth and/or survival of tumorcells of the cancer is enhanced, at least in part, by the activity ofPI3K; in combination with one or more treatments selected from surgery,one or more chemotherapeutic agents, one or more hormone therapies, oneor more antibodies, one or more immunotherapies, radioactive iodinetherapy, and radiation.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, one or morechemotherapeutic agents, one or more hormone therapies, one or moreantibodies, one or more immunotherapies, radioactive iodine therapy, andradiation; where the cancer is selected from breast cancer, coloncancer, rectal cancer, endometrial cancer, gastric carcinoma (includinggastrointestinal carcinoid tumors and gastrointestinal stromal tumors),glioblastoma, hepatocellular carcinoma, small cell lung cancer,non-small cell lung cancer (NSCLC), melanoma, ovarian cancer, cervicalcancer, pancreatic cancer, prostate carcinoma, acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), non-Hodgkin'slymphoma, and thyroid carcinoma. In another embodiment, the invention isdirected to a method of treating cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments independently selected fromsurgery, one or more chemotherapeutic agents, one or more hormonetherapies, one or more antibodies, one or more immunotherapies,radioactive iodine therapy, and radiation; where the cancer is selectedfrom prostate cancer, NSCLC, ovarian cancer, cervical cancer, breastcancer, colon cancer, rectal cancer, and glioblastoma. In anotherembodiment, the invention is directed to a method of treating cancerwhich method comprises administering to a patient a therapeuticallyeffective amount of a Compound of Formula I, as defined in the Summaryof the Invention, in combination with one or more treatmentsindependently selected from surgery, one or more chemotherapeuticagents, one or more hormone therapies, one or more antibodies, one ormore immunotherapies, radioactive iodine therapy, and radiation; wherethe cancer is selected from NSCLC, breast cancer, prostate cancer,glioblastoma, and ovarian cancer.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents independentlyselected from rapamycin, a rapamycin analogue, an alkylating agent, ataxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor. In anotherembodiment, the invention is directed to a method of treating cancerwhich method comprises administering to a patient a therapeuticallyeffective amount of a Compound of Formula I, as defined in the Summaryof the Invention, in combination with a treatment where the treatment isone or two chemotherapeutic agents independently selected fromrapamycin, temozolomide, paclitaxel, docetaxel, carboplatin, cisplatin,oxaliplatin, gefitinib (Iressa®), erlotinib (Tarceva®), Zactima(ZD6474), HKI-272, pelitinib, canertinib, a compound selected from Table4, a compound in Table 7, and lapatinib. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents independently selected from rapamycin,temozolomide, paclitaxel, docetaxel, carboplatin, trastuzumab,erlotinib,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,a compound in Table 7, and lapatinib. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents independently selected from rapamycin,paclitaxel, carboplatin, erlotinib, andN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents independentlyselected from a platin and a taxane. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents independently selected from carboplatin,cisplatin, oxaliplatin, and paclitaxel.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agent is an AKT inhibitor. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents is anAKT inhibitor selected from perifosine, PKC 412, a compound in Table 2a,and a compound in Table 2b.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is a cMET inhibitor. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents is acMET inhibitor selected from a compound in Table 3a, a compound in Table3b, and a compound in Table 3c.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is an EGFR inhibitor. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents is anEGFR inhibitor selected from lapatinib (Tykerb®), gefitinib (Iressa®),erlotinib (Tarceva®), Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI1033, a compound selected from Table 4, and a compound in Table 7. Inanother embodiment, In another embodiment, the invention is directed toa method of treating cancer which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with atreatment where the treatment is one or two chemotherapeutic agentswhere one of the chemotherapeutic agents is an EGFR inhibitor selectedfrom lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®),Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI 1033,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,andN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is an ErbB2 inhibitor. In another embodiment,the invention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents is anErbB2 inhibitor selected from lapatinib, EKB-569, HKI272, CI 1033,PKI-166, and a compound selected from Table 4.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is an HSP90 inhibitor. In another embodiment,the invention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents is anHSP90 inhibitor selected from 17-AAG, 17-DMAG, Geldanamycin, andCNF2024. In another embodiment, the invention is directed to a method oftreating cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is an HSP90 inhibitor selected from 17-AAG,17-DMAG, and Geldanamycin.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is an IGF1R inhibitor. In another embodiment, Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is an IGF1R inhibitor selected from Table 5a andTable 5b.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is a Raf inhibitor. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents is aRaf inhibitor selected from sorafenib, RAF 265 (CHIR-265), and acompound in Table 6.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is a VEGFR inhibitor. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents is aVEGFR inhibitor selected from VEGF Trap, ZD6474 (Zactima), cediranib(AZ2171), pazopanib, sunitinib, sorafenib, axitinib, AEE788, RAF 265(CHIR-265), a compound selected from Table 4, and a compound selectedfrom Table 7.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is a cKIT inhibitor. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents is acKIT inhibitor selected from imatinib, sunitinib, nilotinib, AMG 706,sorafenib, a compound in Table 3b, a compound in Table 3c, a compound inTable 8, and a compound in Table 9.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is a FLT3 inhibitor. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents is aFLT3 inhibitor selected from CEP-701, PKC 412, sunitinib, MLN 518,sunitinib, sorafenib, a compound in Table 3a, a compound in Table 3b, acompound in Table 3c, and a compound in Table 9.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is selected from rapamycin, a rapamycinanalogue, PI103, and SF 1126. In another embodiment, the invention isdirected to a method of treating cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with a treatment where the treatment is one or twochemotherapeutic agents where one of the chemotherapeutic agents isselected from rapamycin, CCI-779, AP 23573, RAD 001, TAFA 93, PI103, andSF 1126. In another embodiment, the invention is directed to a method oftreating cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is rapamycin.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is of formula 100:

where q is 1, 2, or 3; E is —NR⁹—, —O—, or absent and Y is —CH₂CH₂—,—CH₂—, or absent provided that when E is —NR⁹— or —O—, then Y is—CH₂CH₂—; R² is selected from halogen, trihalomethyl, —CN, —NO₂, —OR³,and lower alkyl; R⁸ is selected from —H, lower alkyl, —C(O)OR³,—C(O)N(R³)R⁴, —SO₂R⁴, and —C(O)R³; R⁹ is hydrogen or lower alkyl; R³ ishydrogen or R⁴; R⁴ is selected from lower alkyl, aryl, lower arylalkyl,heterocyclyl, and lower heterocyclylalkyl; or R³ and R⁴, when takentogether with a common nitrogen to which they are attached, form a five-to seven-membered heterocyclyl, said five- to seven-memberedheterocyclyl optionally containing one or more additional heteroatomselected from N, O, S, and P; or a single geometric isomer,stereoisomer, racemate, enantiomer, or diastereomer, thereof andoptionally as a pharmaceutically acceptable salt, additionallyoptionally as a solvate, and additionally as a hydrate thereof. Theterms used to describe the scope of formula 100 are defined in WO2004/006846 (US Nat'l Stage application Ser. No. 10/522,004) which isherein incorporated by reference. Whenever a compound of formula 100 isdescribed in this application, whether by structure or by use of theterm “formula 100,” the terms used to describe that compound are definedby WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004). Inparticular, “alkyl” in formula 100 is intended to include linear,branched, or cyclic hydrocarbon structures and combinations thereof,inclusively; “lower alkyl” means alkyl groups of from one to six carbonatoms. “Aryl” in formula 100 means an aromatic six- to fourteen-memberedcarbocyclic rings which include, for example, benzene, naphthalene,indane, tetralin, fluorene and the like. “Lower arylalkyl” in formula100 means a residue in which an aryl moiety is attached to a parentstructure via one of an alkylene, alkenylene, or alkynylene radicalwhere the “alkyl” portion of the group has one to six carbons; examplesinclude benzyl, phenethyl, phenylvinyl, phenylallyl and the like. Informula 100, “heterocyclyl” means a stable monocyclic, bicyclic ortricyclic three- to fifteen-membered ring radical (including fused orbridged ring systems) that consists of carbon atoms and from one to fiveheteroatoms selected from the group consisting of nitrogen, phosphorus,oxygen and sulfur where the nitrogen, phosphorus, carbon and sulfuratoms in the heterocyclyl radical may be optionally oxidized to variousoxidation states and the nitrogen atom may be optionally quaternized;and the ring radical may be partially or fully saturated or aromatic.“Lower heterocyclylalkyl” means a residue in which a heterocyclyl isattached to a parent structure via one of an alkylene, alkenylene, andalkynylene radical having one to six carbons.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is selected from a compound in Table 2a. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two chemotherapeutic agents where one of the chemotherapeutic agentsis selected from Table 2a.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 2b. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 2b.

In another embodiment, the invention is directed to a method of treatingcancer. which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 3a. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 3a.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 3b. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 3b.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 3c. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 3c.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents is selected from a compound in Table 4. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two chemotherapeutic agents where one of the chemotherapeutic agentsis selected from Table 4.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents isN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,orN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,optionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof. In another embodiment, the invention is directed to a method oftreating cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two chemotherapeutic agents where one of the chemotherapeutic agentsisN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,orN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,optionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two chemotherapeutic agents where one of thechemotherapeutic agents isN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineoptionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof. In another embodiment, the invention is directed to a method oftreating cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two chemotherapeutic agents where one of the chemotherapeutic agentsisN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineoptionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 5a. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 5a.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 5b. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 5b.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 6. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 6.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 7. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 7.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 8. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 8.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is selected from a compound in Table 9. Inanother embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor more chemotherapeutic agents where one of the chemotherapeutic agentis selected from Table 9.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two chemotherapeutic agents where one of the chemotherapeutic agentis paclitaxel.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two chemotherapeutic agents where one of the chemotherapeutic agentis rapamycin.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two chemotherapeutic agents where one of the chemotherapeutic agentis carboplatin.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two chemotherapeutic agents where one of the chemotherapeutic agentis erlotinib.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two chemotherapeutic agents where one of the chemotherapeutic agentis lapatinib.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two antibodies where one of the antibodies is trastuzumab.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two antibodies where one of the antibodies is cetuximab.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two antibodies where one of the antibodies is panitumumab.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two antibodies where one of the antibodies is bevacizumab.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is radiation. In another embodiment, the invention isdirected to a method of treating cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I selected from Table 1 in combination with atreatment where the treatment is radiation.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two antibodies. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twoantibodies independently selected from an IGF1R antibody (including, forexample, ^(α)IGF-1R A12 MoAb, ^(α)IGF-1R 19D12 MoAb, ^(α)IGF-1R h7C10MoAb and ^(α)IGF-1R CP-751871 MoAb), Alemtuzumab, Bevacizumab(Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan,Panitumumab, Rituximab, Tositumomab, Omnitarg (pertuzimab), ananti-ErbB2 antibodies (including trastuzumab (Herceptin®)), and ananti-EGFR antibodies (including, for example, cetuximab (Erbitux),panitumumab, nimotuzumab, and EMD72000)).

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two antibodies. In another embodiment, the invention is directed to amethod of treating cancer which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula Iselected from Table 1 in combination with a treatment where thetreatment is one or two antibodies independently selected from an IGF1Rantibody (including, for example, ^(α)IGF-1R A12 MoAb, ^(α)IGF-1R 19D12MoAb, ^(α)IGF-1R h7C10 MoAb and ^(α)IGF-1R CP-751871 MoAb), Alemtuzumab,Bevacizumab (Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomabtiuxetan, Panitumumab, Rituximab, Tositumomab, Omnitarg (pertuzimab), ananti-ErbB2 antibodies (including trastuzumab (Herceptin®)), and ananti-EGFR antibodies (including, for example, cetuximab (Erbitux),panitumumab, nimotuzumab, and EMD72000)).

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or more chemotherapeutic agents where one of thechemotherapeutic agent is temozolomide. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I selected from Table 1 in combination with atreatment where the treatment is one or more chemotherapeutic agentswhere one of the chemotherapeutic agent is temozolomide.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is surgery. In another embodiment, the invention isdirected to a method of treating cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I selected from Table 1 in combination with atreatment where the treatment is surgery.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment wherethe treatment is one or two hormone therapies. In another embodiment,the invention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twohormone therapies independently selected from tamoxifen, Toremifene(Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarianablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH)analog (including goserelin and leuprolide), Megestrol acetate (Megace),and one or more aromatase inhibitor. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with a treatment where the treatment is one or twohormone therapies where one of the hormone therapies is an aromataseinhibitor selected from letrozole (Femara), anastrozole (Arimidex), andexemestane (Aromasin). In another embodiment, the invention is directedto a method of treating cancer which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with atreatment where the treatment is one or two hormone therapiesindependently selected from tamoxifen and an aromatase inhibitor.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where the treatment is oneor two hormone therapies. In another embodiment, the invention isdirected to a method of treating cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I selected from Table 1 in combination with atreatment where one of the treatments is one or two hormone therapiesindependently selected from tamoxifen, Toremifene (Fareston),Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation,Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analog(including goserelin and leuprolide), Megestrol acetate (Megace), andone or two aromatase inhibitor. In another embodiment, the invention isdirected to a method of treating cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I selected from Table 1 in combination with atreatment where one of the treatments is one or two hormone therapieswhere one of the hormone therapies is an aromatase inhibitor selectedfrom letrozole (Femara), anastrozole (Arimidex), and exemestane(Aromasin). In another embodiment, the invention is directed to a methodof treating cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I selectedfrom Table 1 in combination with a treatment where one of the treatmentsis one or two hormone therapies independently selected from tamoxifenand an aromatase inhibitor.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with a treatment whereone of the treatments is one antibody selected from an EGFR antibody andan ErbB2 antibody, or the treatment is one or two chemotherapeuticagents independently selected from a rapamycin, a rapamycin analogue, analkylating agent, a taxane, a platin, an

EGFR inhibitor, and an ErbB2 inhibitor. In another embodiment, theinvention is directed to a method of treating cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I selected from Table 1 in combination with atreatment where one of the treatments is one antibody selected from anEGFR antibody and an ErbB2 antibody, or the treatment is one or twochemotherapeutic agents independently selected from a rapamycin,rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFRinhibitor, and an ErbB2 inhibitor.

In another embodiment, the invention is directed to a method of treatingacute myelogenous leukemia (AML) which method comprises administering toa patient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments independently selected from bone marrow or peripheralblood stem cell transplantation, radiation, one or two antibodies, andone or two chemotherapeutic agents. In another embodiment, the inventionis directed to a method of treating acute myelogenous leukemia (AML)which method comprises administering to a patient a therapeuticallyeffective amount of a Compound of Formula I, as defined in the Summaryof the Invention, in combination with one or two treatments where one ofthe treatments is one antibody selected from Gemtuzumab ozogamicin(Mylotarg), ^(α)IGF-1R A12 MoAb, ^(α)IGF-1R 19D12 MoAb, ^(α)IGF-1R h7C10MoAb, ^(α)IGF-1R CP-751871 MoAb and trastuzumab. In another embodiment,the invention is directed to a method of treating acute myelogenousleukemia (AML) which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two chemotherapeuticagents selected from Imatinib (i.e. Gleevec®), PKC 412, CEP-701,daunorubicin, doxorubicin, cytarabine (ara-C), an anthracycline drugsuch as daunorubicin or idarubicin (Daunomycin, Idamycin),6-thioguanine, and a granulocyte colony-stimulating factor (such asNeupogen or Leukine).

In another embodiment, the invention is directed to a method of treatingchronic myelogenous leukemia (CML) which method comprises administeringto a patient a therapeutically effective amount of a Compound of FormulaI, as defined in the Summary of the Invention, in combination with oneor more treatments independently selected from bone marrow or peripheralblood stem cell transplantation, radiation, one or two chemotherapeuticagents, immunotherapy, and one or two antibodies. In another embodiment,the invention is directed to a method of treating chronic myelogenousleukemia (CML) which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two of thechemotherapeutic agents selected from Imatinib (i.e. Gleevec®), PKC 412,hydroxyurea (Hydrea), cytosine, cytosine arabinoside, dasatinib, AMN107,VX680 (MK0457), and cytarabine (ara-C). In another embodiment, theinvention is directed to a method of treating chronic myelogenousleukemia (CML) which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two chemotherapeuticagents selected from Imatinib (i.e. Gleevec®) and dasatinib. In anotherembodiment, the invention is directed to a method of treating chronicmyelogenous leukemia (CML) which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is immunotherapy and theimmunotherapy is interferon therapy such as interferon-α.

In another embodiment, the invention is directed to a method of treatingprostate cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments independently selected from surgery (including cryosurgery),radiation, one or two chemotherapeutic agents, one or two antibodies,and one or two hormone therapies. In another embodiment, the inventionis directed to a method of treating prostate cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with one or more treatments where one of the treatmentsis an antibody selected from ^(α)IGF-1R A12 MoAb, ^(α)IGF-1R 19D12 MoAb,^(α)IGF-1R h7C10 MoAb, and ^(α)IGF-1R CP-751871 MoAb. In anotherembodiment, the invention is directed to a method of treating prostatecancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two of thechemotherapeutic agents independently selected from rapamycin,mitoxantrone, prednisone, docetaxel (Taxotere), doxorubicin, etoposide,vinblastine, paclitaxel, and carboplatin. In another embodiment, theinvention is directed to a method of treating prostate cancer whichmethod comprises administering to a patient a therapeutically effectiveamount of a Compound of Formula I, as defined in the Summary of theInvention, in combination with one or more treatments where one of thetreatments is one or two of the hormone therapy independently selectedfrom androgen deprivation therapy and androgen suppression therapy. Inanother embodiment, the invention is directed to a method of treatingprostate cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two chemotherapeuticagents where one of the chemotherapeutic agents is a taxane. In anotherembodiment, the invention is directed to a method of treating prostatecancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two chemotherapeuticagents where one of the chemotherapeutic agents is rapamycin.

In another embodiment, the invention is directed to a method of treatingmelanoma which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, radiation, one or twoimmunotherapies, one or two hormone therapies, and one or twochemotherapeutic agents. In another embodiment, the invention isdirected to a method of treating melanoma which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments where one of the treatments isone or two chemotherapeutic agents independently selected from analkylating agent, a taxane, a platin, and a Raf inhibitor. In anotherembodiment, the invention is directed to a method of treating melanomawhich method comprises administering to a patient a therapeuticallyeffective amount of a Compound of Formula I, as defined in the Summaryof the Invention, in combination with one or more treatments where oneof the treatments is one or two chemotherapeutic agents independentlyselected from sorafenib, Paclitaxel (Taxol®), Docetaxel (Taxotere®),dacarbazine, rapamycin, imatinib mesylate (Gleevec®), sorafenib,cisplatin, carboplatin, dacarbazine (DTIC), carmustine (BCNU),vinblastine, temozolomide (Temodar), Melphalan, and imiquimod (Aldara).In another embodiment, the invention is directed to a method of treatingmelanoma which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two immunotherapiesindependently selected from ipilimumab, interferon-alpha andinterleukin-2. In another embodiment, the invention is directed to amethod of treating melanoma which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is hormone therapy where thehormone therapy is tamoxifen.

In another embodiment, the invention is directed to a method of treatingcolon or rectal cancer which method comprises administering to a patienta therapeutically effective amount of a Compound of Formula I, asdefined in the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, radiation, one or twoantibodies, and one or two chemotherapeutic agents. In anotherembodiment, the invention is directed to a method of treating colon orrectal cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is surgery selected from localexcision, electrofulguration, segmental colon resection, polypectomy,local transanal resection, low anterior resection, abdominoperinealresection, and pelvic exenteration. In another embodiment, the inventionis directed to a method of treating colon or rectal cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with one or more treatments where one of the treatmentsis one or two chemotherapeutic agents independently selected from aplatinum-containing compound (including cisplatin, oxaliplatin, andcarboplatin), 5-fluorouracil (5-FU), leucovorin, capecitabine (Xeloda),irinotecan (Camptosar), FOLFOX (Folinic acid, 5-FU, Oxaliplatin), andleucovorin. In another embodiment, the invention is directed to a methodof treating colon or rectal cancer which method comprises administeringto a patient a therapeutically effective amount of a Compound of FormulaI, as defined in the Summary of the Invention, in combination with oneor more treatments where one of the treatments is one or two antibodiesindependently selected from cetuximab (Erbitux) and bevacizumab(Avastin).

In another embodiment, the invention is directed to a method of treatingpancreatic cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, radiation, one or twoantibodies, and one or two chemotherapeutic agents. In anotherembodiment, the invention is directed to a method of treating pancreaticcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is selected from one or twochemotherapeutic agents independently selected from platinum-containingcompound (including cisplatin, oxaliplatin, and carboplatin),5-fluorouracil (5-FU), gemcitabine, a taxane (including paclitaxel anddocetaxel), topotecan, irinotecan, capecitabine, streptozocin, erlotinib(Tarceva), leucovorin, and capecitabine (Xeloda). In another embodiment,the invention is directed to a method of treating pancreatic cancerwhich method comprises administering to a patient a therapeuticallyeffective amount of a Compound of Formula I, as defined in the Summaryof the Invention, in combination with one or more treatments where oneof the treatments is an antibody where the antibody is cetuximab.

In another embodiment, the invention is directed to a method of treatingbreast cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, radiation, one or twochemotherapeutic agents, one or two hormone therapies, and one or twoantibodies. In another embodiment, the invention is directed to a methodof treating breast cancer which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is one or two of thechemotherapeutic agents independently selected from lapatinib (Tykerb®),Paclitaxel (Taxol®), docetaxel, capecitabine, Cyclophosphamide(Cytoxan), CMF (cyclophosphamide, fluoruracil, and methotrexate),methotrexate, fluorouracil, doxorubicin, epirubicin, gemcitabine,carboplatin (Paraplatin), cisplatin (Platinol), vinorelbine (Navelbine),capecitabine (Xeloda), pegylated liposomal doxorubicin (Doxil),albumin-bound paclitaxel (Abraxane), AC (adriamycin andCyclophosphamide), adriamyclin, and pamidronate or zoledronic acid (totreat bone weakness). In another embodiment, the invention is directedto a method of treating breast cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments where one of the treatments isone or two hormone therapies independently selected from tamoxifen,Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate(Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasinghormone (LHRH) analogs (including goserelin and leuprolide), Megestrolacetate (Megace), and one or more aromatase inhibitors. In anotherembodiment, the invention is directed to a method of treating breastcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two hormone therapiesand one of the hormone therapies is an aromatase inhibitor selected fromletrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin).In another embodiment, the invention is directed to a method of treatingbreast cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two antibodiesindependently selected from ^(α)IGF-1R A12 MoAb, ^(α)IGF-1R 19D12 MoAb,^(α)IGF-1R h7C10 MoAb, ^(α)IGF-1R CP-751871 MoAb, bevacizumab (Avastin),and trastuzumab.

In another embodiment, the invention is directed to a method of treatingbreast cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two chemotherapeuticagents and one of the chemotherapeutic agents is erlotinib.

In another embodiment, the invention is directed to a method of treatingbreast cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two of thechemotherapeutic agents and one or two of the chemotherapeutic agentsare independently selected from rapamycin, lapatinib, erlotinib,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineoptionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineoptionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineoptionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof, andN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineoptionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof.

In another embodiment, the invention is directed to a method of treatingbreast cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two of the antibodies.In another embodiment, the invention is directed to a method of treatingbreast cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two antibodies and oneof the antibodies is trastuzumab.

In another embodiment, the invention is directed to a method of treatingbreast cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two of thechemotherapeutic agents and one of the chemotherapeutic agents isselected fromN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,andN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;optionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof.

In another embodiment, the invention is directed to a method of treatingbreast cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two of thechemotherapeutic agents and one of the chemotherapeutic agents isN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineoptionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof.

In another embodiment, the invention is directed to a method of treatingnon-small cell lung cancer which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments independently selected from surgery, radiation, one ormore antibodies, and one or more chemotherapeutic agents. In anotherembodiment, the invention is directed to a method of treating non-smallcell lung cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two chemotherapeuticagents independently selected from cisplatin, oxaliplatin, carboplatin,Zactima (ZD6474), Paclitaxel, Docetaxel (Taxotere®), Gemcitabine(Gemzar®), Vinorelbine, Irinotecan, Etoposide, Vinblastine, Erlotinib(Tarceva®), gefitinib (Iressa), and Pemetrexed. In another embodiment,the invention is directed to a method of treating non-small cell lungcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is an antibody and the antibodyis Bevacizumab. In another embodiment, the invention is directed to amethod of treating non-small cell lung cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments where one of the treatments isone or two chemotherapeutic agents independently selected fromcisplatin, oxaliplatin, carboplatin, Paclitaxel, Docetaxel (Taxotere®),and erlotinib (Tarceva®).

In another embodiment, the invention is directed to a method of treatingnon-small cell lung cancer which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is one or twochemotherapeutic agents and one of the chemotherapeutic agents iscarboplatin.

In another embodiment, the invention is directed to a method of treatingnon-small cell lung cancer which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is one or twochemotherapeutic agents and one of the chemotherapeutic agents isselected fromN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine,andN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;optionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof. In another embodiment, the invention is directed to a method oftreating non-small cell lung cancer which method comprises administeringto a patient a therapeutically effective amount of a Compound of FormulaI, as defined in the Summary of the Invention, in combination with oneor more treatments where one of the treatments is one or twochemotherapeutic agents and one of the chemotherapeutic agents isN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineoptionally as a pharmaceutically acceptable salt and additionallyoptionally as a hydrate and additionally optionally as a solvatethereof.

In another embodiment, the invention is directed to a method of treatingsmall cell lung cancer which method comprises administering to a patienta therapeutically effective amount of a Compound of Formula I, asdefined in the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, radiation, and one ortwo chemotherapeutic agents. In another embodiment, the invention isdirected to a method of treating small cell lung cancer which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with one or more treatments where one of the treatmentsis one or two chemotherapy agents independently selected from a platin(such as cisplatin, oxaliplatin, and carboplatin), gefitinib,vinorelbine, docetaxel, paclitaxel, etoposide, fosfamide, ifosfamide,cyclophosphamide, cyclophosphamide/doxorubicin/vincristine (CAV),doxorubicin, vincristine, gemcitabine, paclitaxel, vinorelbine,topotecan, irinotecan, methotrexate, and docetaxel.

In another embodiment, the invention is directed to a method of treatingpapillary or anaplastic thyroid cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments independently selected fromsurgery, radiation, radioactive iodine therapy, one or two hormonetherapies, and one or two chemotherapeutic agents. In anotherembodiment, the invention is directed to a method of treating papillaryor anaplastic thyroid cancer which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is one or twochemotherapeutic agents independently selected from thyroid hormonepills, Doxorubucin and a platin. In another embodiment, the invention isdirected to a method of treating papillary or anaplastic thyroid cancerwhich method comprises administering to a patient a therapeuticallyeffective amount of a Compound of Formula I, as defined in the Summaryof the Invention, in combination with one or more treatments where oneof the treatments is hormone therapy and the hormone therapy isradioiodine ablation.

In another embodiment, the invention is directed to a method of treatingendometrial cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, radiation, one or twohormone therapies, and one or two chemotherapeutic agents. In anotherembodiment, the invention is directed to a method of treatingendometrial cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two hormone therapiesindependently selected from megestrol acetate, Tamoxifen, and aprogestin including medroxyprogesterone acetate (Provera) and megestrolacetate (Megace). In another embodiment, the invention is directed to amethod of treating endometrial cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments where one of the treatments isone or two chemotherapeutic agents independently selected from aplatinum-containing compound (including cisplatin, oxaliplatin, andcarboplatin, more for example cisplatin), a taxane (includingpaclitaxel), doxorubicin (Adriamycin), cyclophosphamide, fluorouracil(5-FU), methotrexate, and vinblastine.

In another embodiment, the invention is directed to a method of treatingovarian cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, radiation, one or twoantibodies, and one or two chemotherapeutic agents. In anotherembodiment, the invention is directed to a method of treating ovariancancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is an antibody and the antibodyis bevacizumab. In another embodiment, the invention is directed to amethod of treating ovarian cancer which method comprises administeringto a patient a therapeutically effective amount of a Compound of FormulaI, as defined in the Summary of the Invention, in combination with oneor more treatments where one of the treatments is one or twochemotherapeutic agents independently selected from aplatinum-containing compound (including cisplatin, oxaliplatin andcarboplatin), a taxane (including paclitaxel and docetaxel), topotecan,an anthracyclines (including doxorubicin and liposomal doxorubicin),gemcitabine, cyclophosphamide, vinorelbine (Navelbine),hexamethylmelamine, ifosfamide, etoposide, bleomycin, vinblastine,ifosfamide, vincristine, and cyclophosphamide. In another embodiment,the invention is directed to a method of treating ovarian cancer whichmethod comprises administering to a patient a therapeutically effectiveamount of a Compound of Formula I, as defined in the Summary of theInvention, in combination with one or more treatments where one of thetreatments is one or two chemotherapeutic agents independently selectedfrom a platin and a taxane. In another embodiment, the invention isdirected to a method of treating ovarian cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments where one of the treatments isone or two chemotherapeutic agents independently selected fromcisplatin, oxaliplatin, carboplatin, paclitaxel, and docetaxel.

In another embodiment, the invention is directed to a method of treatingglioblastoma which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, radiation, one or twochemotherapeutic agents, one or two anti-seizure agents, and one or twoagents to reduce swelling. In another embodiment, the invention isdirected to a method of treating glioblastoma which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments where one of the treatments isradiation selected from external beam radiation, interstitialradiotherapy, and stereotactic radiosurgery. In another embodiment, theinvention is directed to a method of treating glioblastoma which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with one or more treatments where one of the treatmentsis one or two chemotherapeutic agents independently selected fromcarmustine (BCNU), Erlotinib (Tarceva), bevacizumab, gefitinib (Iressa),rapamycin, temozolomide, cisplatin, BCNU, lomustine, procarbazine, andvincristine. In another embodiment, the invention is directed to amethod of treating glioblastoma which method comprises administering toa patient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is an anti-seizure agent andthe anti-seizure agent is diphenylhydantoin (Dilantin). In anotherembodiment, the invention is directed to a method of treatingglioblastoma which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is an agents to reduce swellingand the agent is dexamethasone (Decadron). In another embodiment, theinvention is directed to a method of treating glioblastoma which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with one or more treatments where one of the treatmentsis one or two chemotherapeutic agents. In another embodiment, theinvention is directed to a method of treating glioblastoma which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with one or more treatments where one of the treatmentsis one or two chemotherapeutic agents independently selected fromerlotinib and temozolomide.

In another embodiment, the invention is directed to a method of treatingcervical cancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments independently selected from surgery, radiation, and one ortwo chemotherapeutic agents. In another embodiment, the invention isdirected to a method of treating cervical cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments where one of the treatments issurgery selected from cryosurgery, laser surgery, loop electrosurgicalexcision, conization, simple hysterectomy, and radical hysterectomy andpelvic lymph node dissection. In another embodiment, the invention isdirected to a method of treating cervical cancer which method comprisesadministering to a patient a therapeutically effective amount of aCompound of Formula I, as defined in the Summary of the Invention, incombination with one or more treatments where one of the treatments isradiation selected from called external beam radiation therapy andbrachytherapy. In another embodiment, the invention is directed to amethod of treating cervical cancer which method comprises administeringto a patient a therapeutically effective amount of a Compound of FormulaI, as defined in the Summary of the Invention, in combination with oneor more treatments where one of the treatments is one or twochemotherapeutic agents independently selected from a platinum compound(such as cisplatin, carboplatin, and oxaliplatin), paclitaxel,topotecan, ifosfamide, gemcitabine, vinorelbine, and fluorouracil.

In another embodiment, the invention is directed to a method of treatinga gastrointestinal carcinoid tumor which method comprises administeringto a patient a therapeutically effective amount of a Compound of FormulaI, as defined in the Summary of the Invention, in combination with oneor more treatments independently selected from surgery, radiation,immunotherapy, and one or two chemotherapeutic agents. In anotherembodiment, the invention is directed to a method of treating agastrointestinal carcinoid tumor which method comprises administering toa patient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is surgery selected fromexcision and electrofulguration. In another embodiment, the invention isdirected to a method of treating a gastrointestinal carcinoid tumorwhich method comprises administering to a patient a therapeuticallyeffective amount of a Compound of Formula I, as defined in the Summaryof the Invention, in combination with one or more treatments where oneof the treatments is one or two chemotherapeutic agents independentlyselected from cyproheptadine, SOM230, octreotide and lanreotide. Inanother embodiment, the invention is directed to a method of treating agastrointestinal carcinoid tumor which method comprises administering toa patient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is immunotherapy and theimmunotherapy is an interferon.

In another embodiment, the invention is directed to a method of treatinga gastrointestinal stromal tumor which method comprises administering toa patient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments independently selected from surgery, radiation, and oneor two chemotherapeutic agents. In another embodiment, the invention isdirected to a method of treating a gastrointestinal stromal tumor whichmethod comprises administering to a patient a therapeutically effectiveamount of a Compound of Formula I, as defined in the Summary of theInvention, in combination with one or more treatments where one of thetreatments is one or two chemotherapeutic agents independently selectedfrom imatinib mesylate (Gleevec), sunitinib (Sutent), and nilotinib(AMN107).

In another embodiment, the invention is directed to a method of treatinghepatocellular carcinoma which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments independently selected from surgery, radiofrequencyablation, ethanol ablation, cryosurgery, hepatic artery embolization,chemoembolization, radiation, and one or two chemotherapeutic agents. Inanother embodiment, the invention is directed to a method of treatinghepatocellular carcinoma which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I,as defined in the Summary of the Invention, in combination with one ormore treatments where one of the treatments is surgery selected fromresection and transplantation. In another embodiment, the invention isdirected to a method of treating hepatocellular carcinoma which methodcomprises administering to a patient a therapeutically effective amountof a Compound of Formula I, as defined in the Summary of the Invention,in combination with one or more treatments where one of the treatmentsis one or two chemotherapeutic agents independently selected fromsorafenib, 5-fluorouracil and cisplatin.

In another embodiment, the invention is directed to a method of treatingnon-Hodgkin's lymphoma which method comprises administering to a patienta therapeutically effective amount of a Compound of Formula I, asdefined in the Summary of the Invention, in combination with one or moretreatments independently selected from radiation, one or twochemotherapeutic agents, interferon therapy, one or two antibodies, andbone marrow or peripheral blood stem cell transplantation. In anotherembodiment, the invention is directed to a method of treatingnon-Hodgkin's lymphoma which method comprises administering to a patienta therapeutically effective amount of a Compound of Formula I, asdefined in the Summary of the Invention, in combination with one or moretreatments where one of the treatments is one or two chemotherapeuticagents selected from CHOP (cyclophosphamide, doxorubicin, vincristineand prednisone), chlorambucil, fludarabine, and etoposide. In anotherembodiment, the invention is directed to a method of treatingnon-Hodgkin's lymphoma which method comprises administering to a patienta therapeutically effective amount of a Compound of Formula I, asdefined in the Summary of the Invention, in combination with one or moretreatments where one of the treatments is an antibody selected fromrituximab, ibritumomab tiuxetan, tositumomab, and alemtuzumab. Inanother embodiment, the invention is directed to a method of treatingnon-Hodgkin's lymphoma which method comprises administering to a patienta therapeutically effective amount of a Compound of Formula I, asdefined in the Summary of the Invention, in combination with one or moretreatments where one of the treatments is an antibody and the antibodyis rituximab.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is radiation and anothertreatment is surgery.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is radiation and anothertreatment is one or two chemotherapeutic agents.

In another embodiment, the invention is directed to a method of treatingcancer which method comprises administering to a patient atherapeutically effective amount of a Compound of Formula I, as definedin the Summary of the Invention, in combination with one or moretreatments where one of the treatments is surgery and another treatmentis one or two chemotherapeutic agents.

For each of the foregoing embodiments, the Compound of Formula I isselected from any of the following embodiments, including from theRepresentative Compounds in Table 1.

One embodiment (A) of the Invention is directed to a Compound of FormulaI where R¹ is hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl. In another embodiment, R¹ is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted arylalkyl, or optionally substitutedheterocycloalkylalkyl. In another embodiment, R¹ is hydrogen, alkyl,alkyl substituted with one or two hydroxy, alkyl substituted withalkoxy, cycloalkyl, arylalkyl, or heterocycloalkylalkyl. In anotherembodiment, R¹ is hydrogen, methyl, ethyl, propyl, isopropyl,2-hydroxypropyl, 3-hydroxypropyl, 2-ethoxyethyl, 3-methoxypropyl,3-ethoxypropyl, 3-isopropoxypropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, benzyl, or 2-piperidin-1-ylethyl. In anotherembodiment, R¹ is ethyl, isopropyl, cyclopentyl, or cyclohexyl. Inanother embodiment, R¹ is ethyl.

Another embodiment (B) of the Invention is directed to a Compound ofFormula I where R² is hydrogen or alkyl where the alkyl is optionallysubstituted with 1, 2, 3, 4, or 5 R⁸ groups. In another embodiment, R²is hydrogen or alkyl where the alkyl is optionally substituted with one,two, or three R⁸ groups. In another embodiment, R² is hydrogen or alkylwhere the alkyl is optionally substituted with one, two, or three R⁸groups; and each R⁸, when present, is independently selected from amino,alkylamino, dialkylamino, and halo. In another embodiment, R² ishydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, 3-aminopropyl,3-(N-methylamino)-propyl, 3-(N,N-dimethylamino)-propyl, 2-fluoroethyl,or 2,2,2-trifluoroethyl. In another embodiment, R² is hydrogen or ethyl.Yet even more preferably, R² is hydrogen.

In another embodiment of the Invention, R² is hydrogen.

In another embodiment of the invention, R² is alkyl optionallysubstituted with 1, 2, 3, 4, or 5, R⁸ groups. In another embodiment, R²is alkyl where the alkyl is optionally substituted with one, two, orthree R⁸ groups; and each R⁸, when present, is independently selectedfrom amino, alkylamino, dialkylamino, and halo. In another embodiment,R² is methyl, ethyl, propyl, isopropyl, tert-butyl, 3-aminopropyl,3-(N-methylamino)-propyl, 3-(N,N-dimethylamino)-propyl, 2-fluoroethyl,or 2,2,2-trifluoroethyl. In another embodiment, R² is ethyl.

Another embodiment (C) of the Invention is directed to a Compound ofFormula I where R⁴ is optionally substituted alkyl. In anotherembodiment, R⁴ is methyl or ethyl. In another embodiment, R⁴ is methyl.

Another embodiment (D) of the Invention is directed to a Compound ofFormula I where R⁶ is acyl. In another embodiment, R⁶ is alkylcarbonyl.In another embodiment, R⁶ is acetyl.

Another embodiment (E) of the Invention is directed to a Compound ofFormula I where R⁶ is phenyl optionally substituted with 1, 2, 3, 4, or5 R⁹ groups. In another embodiment, R⁶ is phenyl optionally substitutedwith one or two R⁹ groups; and each R⁹, when present, is independentlyselected from aryl, halo, alkoxy, aryloxy, and haloalkyl. In anotherembodiment, R⁶ is phenyl optionally substituted with one or two R⁹groups; and each R⁹, when present, is independently selected fromphenyl, fluoro, chloro, methoxy, phenyloxy, and trifluoromethyl. Inanother embodiment, R⁶ is phenyl, phenyl substituted with phenyl,fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, phenylsubstituted with chloro and fluoro, methoxyphenyl, dimethoxyphenyl,phenyloxyphenyl, or trifluoromethylphenyl.

In another embodiment, R⁶ is phenyl, 2-phenyl-phenyl, 3-phenyl-phenyl,4-phenyl-phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluoro-phenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-phenyloxyphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl, or4-trifluoromethylphenyl.

Another embodiment (F) of the Invention is directed to a Compound ofFormula I where R⁶ is phenyl substituted with 1, 2, 3, 4, or 5 R⁹groups.

Another embodiment (G) of the Invention is directed to a Compound ofFormula I where R⁶ is heteroaryl optionally substituted with 1, 2, 3, 4,or 5 R⁹ groups.

Another embodiment (G1) of embodiment G is a Compound of Formula I whereR⁶ is a 6-membered heteroaryl optionally substituted with one or two R⁹.In another embodiment, R⁶ is pyridinyl, pyrazinyl, pyrimidinyl, orpyridazinyl each of which is optionally substituted with one R⁹ whereR⁹, when present, is halo. In another embodiment, R⁶ is pyridiN-2-yl,pyridin-3-yl, pyridiN-4-yl, 3-fluoropyridiN-4-yl, pyrazin-2-yl,pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyridazin-3-yl, or pyridazin-4-yl, each of which is optionallysubstituted with one or two R⁹.

In another embodiment (G2) of embodiment G is a Compound of Formula Iwhere R⁶ is pyrazinyl, pyrimidinyl, or pyridazinyl each of which isoptionally substituted with one R⁹ where R⁹, when present, is halo. Inanother embodiment, R⁶ is pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4-yl.

Another embodiment (G3) of embodiment G is a Compound of Formula I whereR⁶ is 5-membered heteroaryl optionally substituted with one or two R⁹.In another embodiment R⁶ is pyrazolyl, imidazolyl, thienyl, thiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, triazolyl, ortetrazolyl, each of which is optionally substituted with one R⁹ whereR⁹, when present, is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, orhalo. In another embodiment, R⁶ is pyrazol-1-yl, pyrazol-3-yl,pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl,imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl,pyrrol-3-yl, triazol-1-yl, triazol-4-yl, triazol-5-yl, tetrazol-1-yl, ortetrazol-5-yl; each of which is optionally substituted with one R⁹ whereR⁹, when present, is methyl, benzyl, cyano, phenyl,N-tert-butoxycarbonyl, or chloro. In another embodiment, R⁶ ispyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl,imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl,triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which isoptionally substituted with one R⁹ where R⁹, when present, is methyl,benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro.

Another embodiment (G4) of embodiment G is a Compound of Formula I whereR⁶ is thienyl, pyrrolyl, furanyl, pyrazolyl, thiazolyl, isoxazolyl,imidazolyl, triazolyl, or tetrazolyl, each of which is optionallysubstituted with one R⁹ where R⁹, when present, is methyl, benzyl,cyano, phenyl, N-tert-butoxycarbonyl, or chloro. In another embodiment,R⁶ is thien-2-yl, thien-3-yl, pyrrol-2-yl, furan-2-yl, furan-3-yl,pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl,isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, tetrazol-5-yl, each of whichis optionally substituted with one R⁹ where R⁹, when present, is methyl,benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro. In anotherembodiment, R⁶ is thien-2-yl, thien-3-yl, 5-cyano-thien-2-yl,4-methyl-thien-2-yl, 4-methyl-thien-3-yl, 5-chloro-thien-5-yl,5-phenyl-thien-2-yl, pyrrol-2-yl, N-tert-butoxycarbonyl-pyrrol-2-yl,N-methyl-pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3-yl,pyrazol-4-yl, N-benzyl-pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl,thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, tetrazol-5-yl,

Another embodiment (G5) of embodiment G is a Compound of Formula I whereR⁶ is thien-2-yl, thien-3-yl, pyrrol-2-yl, furan-2-yl, furan-3-yl,pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl,isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, or tetrazol-5-yl, each ofwhich is optionally substituted with one R⁹ where R⁹, when present, ismethyl, benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro.

Another embodiment (G6) of embodiment G is a Compound of Formula I whereR⁶ is indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, orbenzoisoxazolyl each of which is optionally substituted with 1, 2, 3, 4,or 5 R⁹ groups. In another embodiment, R⁶ is indol-2-yl, indol-3-yl,indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-2-yl,benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl,benzimidazol-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl,benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzoxazol-2-yl,benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl,benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl,benzoisoxazol-6-yl, or benzoisoxazol-7-yl; each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R⁹ groups. In another embodiment, R⁶is indol-6-yl.

Another embodiment of the Invention (H) is a Compound of Formula 1 whereR′ is hydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkylalkyl, or optionallysubstituted arylalkyl; X is —NH—; R² is hydrogen or alkyl where thealkyl is optionally substituted with one or two R⁸ groups; R⁴ is alkyl;R⁵ is hydrogen; R⁶ is phenyl or heteroaryl wherein the phenyl andheteroaryl are optionally substituted with one, two, or three R⁹ groups;each R⁸, when present, is independently amino, alkylamino, dialkylamino,or halo; and each R⁹, when present, is independently alkyl, arylalkyl,cyano, aryl, alkoxycarbonyl, or halo.

Another embodiment of the Invention (J) is a Compound of Formula 1 whereR⁶ is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl,imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl,triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which isoptionally substituted with 1, 2, 3, 4, or 5 R⁹ groups.

Another embodiment (K) of the Invention is a Compound of Formula I whereR′ is alkyl or cycloalkyl; R⁴ is methyl; and R⁶ is heteroaryl optionallysubstituted with one or two R⁹ groups. In another embodiment, each R⁹,when present, is independently alkyl, arylalkyl, cyano, aryl,alkoxycarbonyl, or halo. In another embodiment, R⁶ is pyrazol-3-yl,pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl,thien-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl,pyrrol-2-yl, pyrrol-3-yl, triazol-4-yl, triazol-5-yl, or tetrazol-5-yl;each of which is optionally substituted with one R⁹ where R⁹, whenpresent, is methyl, benzyl, cyano, phenyl, or N-tert-butoxycarbonyl.

Another embodiment (K1) of embodiment K is a Compound of Formula I whereR² is hydrogen.

Another embodiment (K2) of embodiment K is a Compound of Formula I whereR² is methyl or ethyl.

Another embodiment (L) of the Invention is a Compound of Formula I whereR¹ is alkyl or cycloalkyl; R⁴ is methyl; and R⁶ is phenyl optionallysubstituted with one or two R⁹ groups. In another embodiment each R⁹,when present, is independently halo, alkoxy, or haloalkyl.

Another embodiment (M) of the Invention is a Compound of Formula I whereR¹ is alkyl or cycloalkyl; R⁴ is methyl; and R² is hydrogen.

Another embodiment (N) of the Invention is a Compound of Formula I whereR¹ is alkyl or cycloalkyl; R⁴ is methyl; and R² is optionallysubstituted alkyl.

Representative Compounds

Representative compounds of Formula I and/or II are depicted below. Theexamples are merely illustrative and do not limit the scope of theinvention in any way.

Compounds of the invention are named according to systematic applicationof the nomenclature rules agreed upon by the International Union of Pureand Applied Chemistry (IUPAC), International Union of Biochemistry andMolecular Biology (IUBMB), and the Chemical Abstracts Service (CAS).Names were generated using ACD/Labs naming software 8.00 release,product version 8.08.

Table 1

The Compounds in Table 1 can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 1can be used to practice the invention. In particular, the invention canbe practiced with one or two pharmaceutically acceptable salts of aCompound of Table 1 which salt(s) are formed with one or two acidsindependently selected from hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, acetic acid,trifluoroacetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid,3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid. Any individual compound (and any optional salt, optional solvate,and optional hydrate thereof) in Table 1 can be used in combination withany of the above embodiments.

TABLE 1 Example Structure Name 1

8-ethyl-2-(ethylamino)-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one 2

6-bromo-8-ethyl-4-methyl-2-[(1-methylethyl)amino]pyrido[2,3-d]pyrimidin- 7(8H)-one 3

6-bromo-2-[(1,1-dimethylethyl)amino]-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)- one 4

6-biphenyl-4-yl-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 5

6-(2,4-difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 6

6-(3-chloro-4-fluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one 7

8-ethyl-2-(ethylamino)-4-methyl-6-[4-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one 8

6-(2,4-dichlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one 9

6-(3,4-difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 10

8-ethyl-2-(ethylamino)-4-methyl-6-[2-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one 11

6-bromo-2-{[3- (dimethylamino)propyl]amino}-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 12

8-ethyl-2-(ethylamino)-4-methyl-6-[4-(phenyloxy)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one 13

6-[2,4-bis(methyloxy)phenyl]-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one 14

8-ethyl-2-(ethylamino)-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 15

8-ethyl-2-(ethylamino)-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 16

8-ethyl-2-(ethylamino)-4-methyl-6-[3-(trifluoromethyl)phenyl]pyrido[2,3- d]pyrimidin-7(8H)-one 17

8-ethyl-2-(ethylamino)-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 18

8-ethyl-2-(ethylamino)-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 19

8-ethyl-2-(ethylamino)-4-methyl-6-[3-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one 20

6-(3-chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 21

6-(4-chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 22

8-ethyl-2-(ethylamino)-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 23

8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 24

8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 25

1,1-dimethylethyl 2-[8-ethyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl]-1H-pyrrole-1-carboxylate 26

8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 27

6-(5-chloro-2-thienyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 28

8-ethyl-2-(ethylamino)-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyrimidin-7(8H)-one 29

8-ethyl-2-(ethylamino)-6-(3-fluoropyridiN-4-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 30

8-ethyl-2-(ethylamino)-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 31

8-ethyl-2-(ethylamino)-4-methyl-6-[1-(phenylmethyl)-1H-pyrazol-4-yl]pyrido[2,3- d]pyrimidin-7(8H)-one 32

6-bromo-2-(ethylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one 33

2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 34

8-ethyl-2-(ethylamino)-6-(1H-indol-6-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 35

8-ethyl-2-(ethylamino)-4-methyl-6-(5-phenyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 36

2-(ethylamino)-6-furan-3-yl-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one 37

8-ethyl-2-(ethylamino)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 38

8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)- one 39

8-cyclohexyl-2-(ethylamino)-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 40

6-bromo-2-(ethylamino)-4-methyl-8-[3-(methyloxy)propyl]pyrido[2,3-d]pyrimidin- 7(8H)-one 41

6-bromo-2-(ethylamino)-8-[2- (ethyloxy)ethyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 42

6-bromo-2-(ethylamino)-4-methyl-8-(2-piperidin-1-ylethyl)pyrido[2,3-d]pyrimidin- 7(8H)-one 43

6-bromo-2-(ethylamino)-8-[3- (ethyloxy)propyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 44

6-bromo-2-(ethylamino)-4-methyl-8-{3-[(1-methylethyl)oxy]propyl}pyrido[2,3- d]pyrimidin-7(8H)-one 45

6-bromo-2-(ethylamino)-8-(3-bydroxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 46

6-bromo-2-(ethylamino)-8-(2-hydroxyethyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 47

6-bromo-8-cyclopropyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 48

8-ethyl-2-(ethylamino)-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 49

6-bromo-8-cyclopentyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 50

8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)- one 51

2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one 52

8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)- one 53

2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one 54

8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)- one 55

8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]pyrido[2,3- d]pyrimidin-7(8H)-one 56

2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 57

2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 58

8-ethyl-4-methyl-2-(methylamino)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)- one 59

2-amino-8-cyclopentyl-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)- one 60

8-ethyl-2-[(2-fluoroethyl)amino]-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one 61

2-amino-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)- one 62

2-amino-8-ethyl-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 63

2-amino-4-methyl-8-(phenylmethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)- one 64

2-amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 65

2-amino-8-ethyl-4-methyl-6-(2- thienyl)pyrido[2,3-d]pyrimidin-7(8H)one66

2-amino-8-ethyl-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 67

2-amino-8-ethyl-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 68

2-amino-8-ethyl-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 69

2-amino-8-ethyl-4-methyl-6-(3- thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one70

2-amino-8-ethyl-6-furan-3-yl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one71

2-amino-8-ethyl-4-methyl-6-phenylpyrido[2,3- d]pyrimidin-7(8H)-one 72

2-amino-8-ethyl-4-methyl-6-[4- (methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one 73

2-amino-6-(4-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 74

2-amino-6-(3-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 75

2-amino-8-ethyl-6-isoxazol-4-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 76

2-amino-8-ethyl-6-furan-2-yl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one77

2-amino-6-(2,4-dichlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 78

5-(2-amino-8-ethyl-4-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)thiophene-2-carbonitrile 79

2-amino-8-ethyl-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyrimidin-7(8H)-one 80

2-amino-8-ethyl-6-(1H-imidazol-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 81

2-amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 82

2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 83

2-amino-8-ethyl-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 84

2-amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 85

2-amino-8-ethyl-4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 86

2-amino-6-bromo-8-cyclopentyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one87

2-amino-4,8-diethyl-6-(1H-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one88

2-amino-8-cyclopentyl-4-methyl-6-(1,3-thiazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

Table 2a Representative AKT Inhibitors

The Compounds in Table 2a can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 2acan be used to practice the invention.

TABLE 2a Cmpd No. Name 13-(azetidin-3-ylidenemethyl)-4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 24-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine 34-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-chloropyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine 42-({5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}oxy)-N,N-dimethylethanamine 52-({5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}oxy)-N,N-diethylethanamine 64-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 74-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine 8N-(3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-yn-1-yl)acetamide 9N,N-diethyl-2-({3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}oxy)ethanamine 103-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-methylphenyl}-N,N-diethylpropan-1-amine 113-bromo-4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 123-bromo-4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 132-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-methylphenyl}oxy)-N,N-diethylethanamine 144-[4-(5-chloro-2-methyl-3-{[2-(1-methylpiperidin-4-yl)ethyl]oxy}phenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 155-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 164-(4-{5-chloro-2-methyl-3-[(2-morpholin-4-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 174-(4-{5-chloro-2-methyl-3-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 183-bromo-4-{4-[5-chloro-2-methyl-3-(3-morpholin-4-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 193-bromo-4-(4-{5-chloro-2-methyl-3-[3-(4-methylpiperazin-1-yl)propyl]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 203-bromo-4-(4-{5-chloro-2-methyl-3-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 213-bromo-4-(4-{5-chloro-2-methyl-3-[(2-morpholin-4-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 224-{4-[5-chloro-2-methyl-3-(3-morpholin-4-ylpropyl)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 23N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}-N,N-diethylethane-1,2-diamine 244-{4-[5-chloro-2-methyl-3-(3-piperidin-1-ylpropyl)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 254-[4-(5-chloro-3-{[2-(4-ethylpiperazin-1-yl)ethyl]oxy}-2-methylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 264-(4-{5-chloro-2-methyl-3-[(3-morpholin-4-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 273-bromo-4-{4-[5-chloro-2-methyl-3-(3-piperidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 28N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-methylphenyl}-N,N-diethylethane-1,2-diamine 293-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 304-[4-(5-chloro-2-methyl-3-{[2-(4-methylpiperazin-1-yl)ethyl]oxy}phenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 314-[4-(5-chloro-2-methyl-3-{[(1-methylpiperidin-4-yl)methyl]oxy}phenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 32N,N-diethyl-2-({3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}oxy)ethanamine 332-[(5-chloro-3-{4-[1-(1,1-dimethylethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}-2-methylphenyl)oxy]-N,N-diethylethanamine 342-[(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)oxy]-N,N-diethylethanamine 354-(4-{5-chloro-2-methyl-3-[(3-pyrrolidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 364-[4-(5-chloro-2-methyl-3-{[3-(4-methylpiperazin-1-yl)propyl]oxy}phenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 373-bromo-4-(4-{5-chloro-2-methyl-3-[(3-piperidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 383-bromo-4-(4-{5-chloro-2-methyl-3-[(3-morpholin-4-ylpropyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 394-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 404-(4-{5-chloro-2-methyl-3-[(3-morpholin-4-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 414-(4-{5-chloro-2-methyl-3-[(2-morpholin-4-ylethyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 424-(4-{5-chloro-2-methyl-3-[(3-piperidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 434-[4-(5-chloro-3-{[3-(4-ethylpiperazin-1-yl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 445-chloro-2-methyl-3-[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-pyrrolidin-1-ylethyl)aniline 455-chloro-2-methyl-3-[4-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-pyrrolidin-1-ylethyl)aniline 46N′-(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)-N,N-dimethylethane-1,2-diamine 473-({5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}oxy)-N,N-diethylpropan-1-amine 48N′-(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)-N,N-diethylethane-1,2-diamine 495-chloro-2-methyl-N-(2-pyrrolidin-1-ylethyl)-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}aniline 503-bromo-4-(4-{4-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 514-(4-{4-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 523-methyl-4-(4-{4-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 534-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 544-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine 554-(4-{5-chloro-2-methyl-3-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 563-[(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)oxy]-N,N-diethylpropan-1-amine 575-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 583-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-fluoro-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 594-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 603-bromo-4-{4-[5-fluoro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 614-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 624-(4-{5-chloro-2-methyl-3-[3-(4-methylpiperazin-1-yl)propyl]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 633-bromo-4-(4-pyridin-2-ylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 643-bromo-4-[4-(2,4-dimethylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine653-bromo-4-{4-[3-(methyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine663-bromo-4-{4-[2-(methyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine673-bromo-4-{4-[4-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 684-(4-{5-chloro-2-methyl-3-[(3-pyrrolidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 694-(4-{5-chloro-2-methyl-3-[(3-piperidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 704-[4-(5-chloro-2-methyl-3-{[3-(4-methylpiperazin-1-yl)propyl]oxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 714-[4-(5-chloro-3-{[3-(4-ethylpiperazin-1-yl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 723-bromo-4-[4-(5-chloro-2-methyl-3-{[2-(4-methylpiperazin-1-yl)ethyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 734-[4-(5-chloro-2-methyl-3-{[2-(4-methylpiperazin-1-yl)ethyl]oxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 743-bromo-4-[4-(5-chloro-3-{[2-(4-ethylpiperazin-1-yl)ethyl]oxy}-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 753-bromo-4-[4-(3,4-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine763-bromo-4-[4-(3,4-difluorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine773-bromo-4-[4-(2,4-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine783-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-fluoro-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 795-fluoro-2-methyl-N-(2-pyrrolidin-1-ylethyl)-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}aniline 804-{4-[3,5-bis(methyloxy)phenyl]piperazin-1-yl}-3-bromo-1H-pyrazolo[3,4-d]pyrimidine814-[4-(5-chloro-3-{[2-(4-ethylpiperazin-1-yl)ethyl]oxy}-2-methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 82N-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}-N,N′,N′-trimethylethane-1,2-diamine 833-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-methylphenyl}oxy)-N,N-diethylpropan-1-amine 843-bromo-4-(4-{5-chloro-2-methyl-3-[(3-pyrrolidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 853-bromo-4-[4-(5-chloro-2-methyl-3-{[3-(4-methylpiperazin-1-yl)propyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 863-bromo-4-[4-(5-chloro-3-{[3-(4-ethylpiperazin-1-yl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 873-(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}phenyl)-N,N-diethylpropan-1-amine 883-bromo-4-[4-(5-chloro-2-methyl-3-{[(1-methylpiperidin-4-yl)methyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 893-bromo-4-[4-(5-chloro-2-methyl-3-{[2-(1-methylpiperidin-4-yl)ethyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 904-[4-(5-chloro-2-methyl-3-{[(1-methylpiperidin-4-yl)methyl]oxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 914-[4-(5-chloro-2-methyl-3-{[2-(1-methylpiperidin-4-yl)ethyl]oxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 924-(4-{5-chloro-2-methyl-3-[3-(4-methylpiperazin-1-yl)propyl]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 933-bromo-4-[4-(3-chloro-4-fluorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine941-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}ethanone953-bromo-4-[4-(2,5-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine963-bromo-4-[4-(3,4-dimethylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine973-bromo-4-[4-(4-nitrophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine98 3-ethyl-4-(4-phenylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 993-ethyl-4-{4-[3-(methyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine1004-{4-[5-chloro-2-methyl-3-(3-piperidin-1-ylpropyl)phenyl]piperazin-1-yl}-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 1014-[4-(3,6-dimethylpyrazin-2-yl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine1021-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]isoquinoline1033-bromo-4-[4-(2,6-dimethylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1043-bromo-4-{4-[4-(ethyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine1053-bromo-4-[4-(2-ethylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1064-{4-[2,4-bis(methyloxy)phenyl]piperazin-1-yl}-3-bromo-1H-pyrazolo[3,4-d]pyrimidine1073-bromo-4-(4-pyrazin-2-ylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine1083-bromo-4-(4-pyrimidin-2-ylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine109 4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(trifluoromethyl)quinoline 1103-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyrazine-2-carbonitrile1114-[4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine112 ethyl4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidine-5-carboxylate 1134-{4-[3-chloro-5-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 1144-[4-(3-bromo-2-chloro-5-fluorophenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 1152-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyridine-3-carboxamide1163-ethyl-4-{4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 1173-bromo-4-{4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 1183-bromo-4-{4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 1192-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyrazin-2-yl}oxy)-N,N-dimethylethanamine 1204-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylquinoline1213-bromo-4-[4-(2-nitrophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1222-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]benzonitrile1234-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]benzonitrile1243-bromo-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine1253-bromo-4-(4-{4-[(phenylmethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 1264-{4-[5-chloro-2-methyl-3-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 1272-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyridine-3-carbonitrile1283-bromo-4-[4-(3,5-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1293-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-chloro-5-fluoro-N-(2-pyrrolidin-1-ylethyl)aniline 1302-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-fluoro-N-(2-pyrrolidin-1-ylethyl)aniline 1313-bromo-4-[4-(2,5-difluorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1324-[4-(2,5-difluorophenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine1333-bromo-4-{4-[3-(methyloxy)pyrazin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine1343-bromo-4-[4-(3-chlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1353-bromo-4-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 1363-bromo-4-{4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 1374-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidine 1385-chloro-2-methyl-3-{4-[3-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}-N-(2-pyrrolidin-1-ylethyl)aniline 1392-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}oxy)-N-ethylacetamide 1402-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,N-diethylpyrimidin-4-amine 1413-bromo-4-[4-(3-{[(3-methylphenyl)methyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 1423-bromo-4-(4-{3-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 1433-bromo-4-[4-(4-furan-2-ylpyrimidin-2-yl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1446-{2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyrimidin-4-yl}-2H-1,4-benzoxazin-3(4H)-one 1453-ethyl-4-{4-[2-methyl-3-(methyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 146N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}-N-methyl-N-(1-methylethyl)ethane-1,2-diamine 147N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}-N-ethyl-N-methylethane-1,2-diamine 148N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-methylphenyl}-N,N-dimethylethane-1,2-diamine 1493-({6-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-chloro-5-methylpyrimidin-4-yl}oxy)-N,N-diethylpropan-1-amine 1503-bromo-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1513-bromo-4-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine152 3-bromo-4-(4-phenylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 1533-bromo-4-[4-(4-fluorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1543-bromo-4-[4-(4-chlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1553-bromo-4-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine1564-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine1573-bromo-4-[4-(4-bromophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1583-bromo-4-[3-methyl-4-(3-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine1594-[4-(3-bromo-5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine 1604-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine 1615-chloro-3-[4-(3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 1625-chloro-2-methyl-3-{4-[3-(2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-yl}-N-(2-pyrrolidin-1-ylethyl)aniline 1634-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-(2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine 1643-bromo-4-[(3S)-4-(5-chloro-2-methylphenyl)-3-methylpiperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 1655-bromo-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylaniline1662-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}oxy)-N-cyclopropylacetamide 1673-bromo-4-(4-{3-[(2-piperidin-1-ylethyl)oxy]pyrazin-2-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 1684-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6,7-bis(methyloxy)quinazoline 1692-({3-chloro-5-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}oxy)-N,N-diethylethanamine 1704-{4-[2-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 1713-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(2-methylpropyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline 1723-({4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-chloro-5-methylpyrimidin-2-yl}oxy)-N,N-diethylpropan-1-amine 1733-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(phenylmethyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline 1743-bromo-4-[(3R)-4-(5-chloro-2-methylphenyl)-3-methylpiperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 1753-[(2S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl]-4-methyl-N-phenylbenzamide 1763-[(2S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl]-4-methyl-N-(phenylmethyl)benzamide 177 methyl3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methylbenzoate1783-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methylbenzoicacid 179(2E)-3-(4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)prop-2-enoic acid 1803-(4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)prop-2-yn-1-ol 1814-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-(5-chloro-2-methylphenyl)piperazin-2-one 1823-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(2-methylpropyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline 183N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(2-methylpropyl)oxy]phenyl}-N,N-diethylethane-1,2-diamine 184 methyl3-bromo-5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methylbenzoate 1853-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-phenylbenzamide 1863-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,4-dimethylbenzamide1872-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}oxy)-N,N-diethylethanamine 188 methyl3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzoate 1893-bromo-5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-phenylbenzamide 1903-bromo-5-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-phenylbenzamide 191N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-methylphenyl}-N-methyl-N-(1-methylethyl)ethane-1,2-diamine 1923-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-phenyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 193N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(2-methylpropyl)oxy]phenyl}-N,N-dimethylethane-1,2-diamine 1943-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,N,4-trimethylbenzamide 1953-[4-(3-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-(2-methylpropyl)benzamide 1963-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,N,4-trimethyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 1973-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxopiperazin-1-yl]-4-methyl-N-phenylbenzamide 1983-[(2R)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazin-1-yl]-4-methyl-N-phenylbenzamide 1993-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(pyrrolidin-1-ylcarbonyl)-N-(2-pyrrolidin-1-ylethyl)aniline 2003-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,4-dimethyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 2013-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(4-chlorophenyl)-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 2023-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-chlorophenyl)-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 2033-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(cyclopropylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2043-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(3-methylbutyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline 2053-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2-ethylbutyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2063-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(butyloxy)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2073-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-(1-methylethyl)-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 2083-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,4-dimethyl-N-(1-methylethyl)-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 2093-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(cyclobutylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2103-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(ethyloxy)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2113-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-[2-(dimethylamino)ethyl]-4-methylbenzamide 2123-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(1,1-dimethylethyl)-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 2133-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-pyridin-3-yl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 2143-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2-fluoro-2-methylpropyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2153-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(cyclohexylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2163-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(cyclopentylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2173-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-ethyl-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 2183-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(1-methylethyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline 2193-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2,2-dimethylpropyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2203-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[(tetrahydrofuran-2-ylmethyl)oxy]aniline 2213-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-{[2-(methyloxy)ethyl]oxy}-N-(2-pyrrolidin-1-ylethyl)aniline 2223-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(propyloxy)-N-(2-pyrrolidin-1-ylethyl)aniline 2233-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[2-(dimethylamino)ethyl]amino}-4-methyl-N-phenylbenzamide 224N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2-fluoro-2-methylpropyl)oxy]-2-methylphenyl}-N,N-dimethylethane-1,2-diamine 2253-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[2-(dimethylamino)ethyl]amino}-4-methyl-N-(1-methylethyl)benzamide 2261-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}pentan-1-one 227N′-(3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methylphenyl)-N,N-dimethylethane-1,2-diamine2283-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2295-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-(2-pyrrolidin-1-ylethyl)biphenyl-3-amine 2301-(3-{5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methylbiphenyl-3-yl}propyl)pyridinium 2313-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-(1,3-thiazol-2-yl)aniline 2323-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzoic acid 2333-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(phenylethynyl)-N-(2-pyrrolidin-1-ylethyl)aniline 234{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}(phenyl)methanone 2353-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-ethynyl-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2363-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(3,3-dimethylbut-1-yn-1-yl)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2373-bromo-4-{4-[5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 2383-bromo-4-{4-[2-methyl-5-[(2-methylpropyl)oxy]-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 2393-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-N-(2-pyrrolidin-1-ylethyl)aniline 2403-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(2-pyrrolidin-1-ylethyl)aniline 2411-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}propan-1-one 2423-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(3,3-dimethylbutyl)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2433-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-ethyl-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2443-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[2-(trimethylsilyl)ethyl]aniline 2453-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(2-phenylethyl)-N-(2-pyrrolidin-1-ylethyl)aniline 2461-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}butan-1-one 2473-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,4-dimethyl-N-(methyloxy)-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide 2483-bromo-4-[4-(3-bromo-5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 2494-[4-(3-bromo-5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 2501-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}ethanone 2513-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(difluoromethyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2523-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[(difluoromethyl)oxy]methyl}-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline2533-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(methyloxy)-N-(2-pyrrolidin-1-ylethyl)aniline 2545-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2552-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-3,5,6-trifluoro-N-(3-methylbutyl)pyridin-4-amine 2563-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-[(cyclopropylmethyl)oxy]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide2573-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(2-pyrrolidin-1-ylethyl)aniline 2583-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(ethylsulfonyl)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2593-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(methylsulfonyl)-N-(2-pyrrolidin-1-ylethyl)aniline 2601-{3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}pentan-1-one 2613-bromo-4-[4-(5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 2626-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-3,5-difluoro-N~4~-(3-methylbutyl)-N~2~-(2-pyrrolidin-1-ylethyl)pyridine-2,4-diamine 2633-bromo-5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-pyrrolidin-1-ylethyl)aniline 2643-bromo-4-[4-(3′,4′,6-trifluoro-4-methylbiphenyl-3-yl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 2653-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-N-(2-pyrrolidin-1-ylethyl)aniline 266{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}methanol 2673-bromo-4-(4-{4-methyl-2′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 2683-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[(2,2-difluorocyclopropyl)methyl]oxy}-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline2695-bromo-3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2703-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(ethyloxy)methyl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2713-[4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-1-methyl-6-(trifluoromethyl)-1H-benzimidazol-2-yl]propan-1-ol 2721-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}-4,4,4-trifluorobutan-1-one 273{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}(cyclopropyl)methanone 2743-({3′-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4′-methylbiphenyl-2-yl}oxy)-N,N-dimethylpropan-1-amine 2753-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(1,1-difluorobutyl)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline 2763-bromo-4-(4-{4-methyl-2′-[(3-morpholin-4-ylpropyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 2773-bromo-4-(4-{4-methyl-2′-[(2-morpholin-4-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 2783-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-{[(2,2,2-trifluoroethyl)oxy]methyl}aniline 2791-[2-({3′-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4′-methylbiphenyl-2-yl}oxy)ethyl]pyrrolidine-2,5-dione 2803-bromo-4-(4-{3′-fluoro-4-methyl-2′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 2811-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}butan-1-one 2823-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[(3,3,3-trifluoropropyl)oxy]aniline 2833-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[(2,2,2-trifluoroethyl)oxy]aniline 2841-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]phenyl}butan-1-ol 2853-bromo-4-(4-{4-chloro-2′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 2863-[4-(4-{5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methyl-3-[(2-pyrrolidin-1-ylethyl)amino]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]prop-2-yn-1-ol2873-bromo-4-(4-{4-chloro-4′-fluoro-2′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 2883-bromo-4-(4-{4-methyl-3′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 289(2E)-3-[4-(4-{5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methyl-3-[(2-pyrrolidin-1-ylethyl)amino]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]prop-2-enoicacid 2903-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)-5-[4,4,4-trifluoro-1,1-bis(methyloxy)butyl]aniline291 6-(4-phenylpiperazin-1-yl)-9H-purine 2926-[4-(3-chlorophenyl)piperazin-1-yl]-9H-purine 2934-(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 2944-[4-(3-chlorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine 2954-(4-phenylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 2964-[4-(3-chlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 2976-[4-(2-chlorophenyl)piperazin-1-yl]-9H-purine 2986-[4-(2-fluorophenyl)piperazin-1-yl]-9H-purine 2994-[4-(2-methylphenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine 3004-{4-[2-(methyloxy)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine3014-{4-[3-(methyloxy)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine3024-{4-[4-(methyloxy)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine3034-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine304 6-{4-[4-(methyloxy)phenyl]piperazin-1-yl}-9H-purine 3056-{4-[2-(methyloxy)phenyl]piperazin-1-yl}-9H-purine 3066-[4-(4-chlorophenyl)piperazin-1-yl]-9H-purine 3076-[4-(4-fluorophenyl)piperazin-1-yl]-9H-purine 3084-[4-(4-chlorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine 3094-[4-(2-chlorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine 3104-[4-(4-fluorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine 3114-[4-(2-fluorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine 3126-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-9H-purine 3136-[4-(2-methylphenyl)piperazin-1-yl]-9H-purine 3144-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine315 4-[4-(2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine3164-[4-(3-chlorophenyl)piperazin-1-yl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine3173-methyl-4-[4-(2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine3184-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine3194-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine3204-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-methyl-6-phenyl-1H-pyrazolo[3,4-d]pyrimidine 3214-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine3224-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-6-methyl-1H-pyrazolo[3,4-d]pyrimidine3234-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-6-ethyl-1H-pyrazolo[3,4-d]pyrimidine3244-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-6-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidine 3254-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine3264-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-({[2-(methyloxy)ethyl]oxy}methyl)-1H-pyrazolo[3,4-d]pyrimidine 3273-bromo-4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine3284-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-propyl-1H-pyrazolo[3,4-d]pyrimidine3294-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol 3304-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-N-phenyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine 3314-[4-(3-chlorophenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine3324-{4-[5-chloro-2-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 3333-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol 3344-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-{3-[(phenylmethyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidine 3353-(1,3-benzodioxol-5-yl)-4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 3364-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(2-thienyl)-1H-pyrazolo[3,4-d]pyrimidine3373-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}aniline 3383-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzoic acid 3394-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine 340N-(4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)acetamide 3414-[4-(3-chlorophenyl)-1,4-diazepan-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine3424-[5-(3-chlorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 3434-(4-{3-chloro-4-[(2-morpholin-4-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 344 methyl1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylate 3454-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-methylbut-2-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 3464-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 347 methyl4-(3-chlorophenyl)-1-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylate 3484-(4-{3-chloro-4-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 3494-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidine 3501-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylicacid 3511-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylpiperazine-2-carboxamide 3524-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(phenylmethyl)-1H-pyrazolo[3,4-d]pyrimidine 3534-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine 3544-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidine 3554-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine 3564-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[4-(phenyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidine 3574-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-{4-[(piperidin-4-ylmethyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidine 3581-(3-chlorophenyl)-N-[2-(dimethylamino)ethyl]-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-2-carboxamide 3594-[4-(5-chloro-2-methyl-3-morpholin-4-ylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 3604-(3-chlorophenyl)-1-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylpiperazine-2-carboxamide 3614-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[2-(methyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidine 3624-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-pyridin-4-yl-1H-pyrazolo[3,4-d]pyrimidine 3634-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[3-(methyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidine 3644-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzonitrile 365[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(methyloxy)phenyl]methanol 366 methyl5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(methyloxy)benzoate 367(2E)-3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-enoic acid 3683-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}propanoic acid 3693-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}propan-1-ol 370 methyl(2E)-3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-enoate 3714-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-{4-[(2-morpholin-4-ylethyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidine 3725-chloro-N-[2-(dimethylamino)ethyl]-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(methyloxy)benzamide 3734-(4-{5-chloro-2-(methyloxy)-3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}piperazin-1-yl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 374 2-(dimethylamino)ethyl5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(methyloxy)benzoate 3751-[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(methyloxy)phenyl]-N,N-dimethylmethanamine 376N′-{[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(methyloxy)phenyl]methyl}-N,N-dimethylethane-1,2-diamine 377[1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl]methanol3783-[(4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)oxy]-N,N-dimethylpropan-1-amine 3792-chloro-4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-methylphenol3801-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(1-methylpiperidin-4-yl)piperazine-2-carboxamide 3811-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(2-morpholin-4-ylethyl)piperazine-2-carboxamide 3822-{[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(methyloxy)phenyl]oxy}-N,N-dimethylethanamine 3833-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}-N,N-dimethylprop-2-yn-1-amine 384N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}-N,N-dimethylethane-1,2-diamine 385 1,1-dimethylethyl(2E)-3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-enoate 3863-({2-chloro-4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-methylphenyl}oxy)-N,N-dimethylpropan-1-amine 3872-({2-chloro-4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-methylphenyl}oxy)-N,N-dimethylethanamine 3884-{4-[5-chloro-2-methyl-4-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine 3894-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 3903-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-diethylprop-2-yn-1-amine 3913-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-yn-1-ol 3924-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine 393 phenylmethyl(3aR,6aS)-5-({4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}methylidene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 3944-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[(E)-(3aR,6aS)-hexahydrocyclopenta[c]pyrrol-5(1H)-ylidenemethyl]-1H-pyrazolo[3,4-d]pyrimidine3954-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 3964-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 3973-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-diethylpropan-1-amine 3984-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-pyrrolidin-1-ylpropyl)-1H-pyrazolo[3,4-d]pyrimidine 3994-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine 4003-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylphenyl}-N,N-diethylpropan-1-amine 4014-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine

Table 2b Additional Representative AKT Inhibitors

The Compounds in Table 2b can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 2bcan be used to practice the invention.

TABLE 2b Entry Name 1[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methanol 22-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylethanamine 33-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylpropan-1-amine 43-bromo-4-{4-[(4-bromophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 5 {4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4-chlorophenyl)methyl]piperazin-2-yl}methanol 6N′-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]-N,N-diethylethane-1,2-diamine 73-bromo-4-(4-{[4-(1,1-dimethylethyl)phenyl]methyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 84-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4-chlorophenyl)methyl]piperazin-2-one 92-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]acetamide 10N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-N′,N′-diethylpropane-1,3-diamine 113-bromo-4-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 12N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-N′-[2-(dimethylamino)ethyl]urea 13N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]-N′-[2-(dimethylamino)ethyl]urea 142-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxopiperazin-1-yl]-2-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]acetamide 152-(dimethylamino)ethyl [1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)carbamate 163-bromo-4-{4-[(4-chloro-3-fluorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 173-bromo-4-{4-[(4-chloro-2-fluorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 18N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-N′,N′-diethylethane-1,2-diamine 193-bromo-4-{4-[(4-chlorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 20[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-fluorophenyl)methanone 21N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]-N′,N′-diethyl-N-methylethane-1,2-diamine 22[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-fluorophenyl)methanol 233-bromo-4-(4-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 24N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-N~3~,N~3~-diethyl-beta-alaninamide 252-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-fluorophenyl)methyl]oxy}-N,N-dimethylethanamine 26N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]-N~3~,N~3~-diethyl-beta-alaninamide 273-bromo-4-{4-[(3,4-dichlorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 28N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-N′-[2-(dimethylamino)ethyl]ethanediamide 29N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-2-(diethylamino)ethanesulfonamide 304-[4-(biphenyl-4-ylmethyl)piperazin-1-yl]-3-bromo-1H-pyrazolo[3,4-d]pyrimidine31 3-bromo-4-{(3S)-4-[(4-chlorophenyl)methyl]-3-methylpiperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 323-bromo-4-(4-{[4-(methyloxy)phenyl]methyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 334-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-[3-(trifluoromethyl)phenyl]piperazine-1-carboxamide 343-bromo-4-{4-[(4-fluorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 35N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)pent-4-enamide 363-bromo-4-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 374-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-bromo-1H-pyrazolo[3,4-d]pyrimidine 38[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methanone 393-bromo-4-(4-{[4-(phenyloxy)phenyl]methyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 403-bromo-4-{4-[(3,4-dichlorophenyl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 414-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]methyl}-N,N-dimethylaniline 42 methyl4-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]methyl}benzoate 433-bromo-4-{4-[(2E)-3-phenylprop-2-enoyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 441-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-[(4-chlorophenyl)methyl]-N-[3-(diethylamino)propyl]piperidine-4- carboxamide45 3-bromo-4-{4-[(2-bromophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 463-bromo-4-{4-[(2-chlorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 473-bromo-4-{4-[(2,4-dichlorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 483-bromo-4-{4-[(2-chloro-4-fluorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 491-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-(4-chlorophenyl)-N-[3-(diethylamino)propyl]piperidine-4-carboxamide 503-bromo-4-[4-(phenylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4- d]pyrimidine51 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-pyridin-2-ylacetamide 523-bromo-4-[4-(1H-imidazol-2-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 533-bromo-4-(4-{[3-(phenyloxy)phenyl]methyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 543-bromo-4-{4-[(3-methylphenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 553-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]methyl}benzonitrile 563-bromo-4-{4-[(2-chloro-6-fluorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 573-bromo-4-[4-(1-phenylethyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 583-bromo-4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 59 1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(4-chlorophenyl)piperidin-4-amine 603-bromo-4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 613-bromo-4-(4-{[2,3,4-tris(methyloxy)phenyl]methyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 623-bromo-4-[4-({3-[(phenylmethyl)oxy]phenyl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 633-bromo-4-[4-(naphthalen-1-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 643-bromo-4-(4-{[5-(4-chlorophenyl)furan-2-yl]methyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 653-bromo-4-[4-({4-[(4-fluorophenyl)oxy]-3-nitrophenyl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 663-bromo-4-[4-(furan-2-ylcarbonyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 673-bromo-4-[4-(1H-indol-6-ylcarbonyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 683-bromo-4-{4-[2-(2-thienyl)ethyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 693-bromo-4-[4-(3-pyrrolidin-1-ylpropyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 703-bromo-4-[4-(cyclohexylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 713-bromo-4-{4-[(10-chloroanthracen-9-yl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 723-bromo-4-[4-(1-methylpropyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 734-(4-{[4,6-bis(methyloxy)pyrimidin-2-yl]methyl}piperazin-1-yl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidine 743-bromo-4-{4-[2-(methyloxy)ethyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 753-bromo-4-[4-(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 763-bromo-4-{4-[3-(methyloxy)propyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 774-{4-[[4,6-bis(methyloxy)pyrimidin-2-yl](phenyl)methyl]piperazin-1-yl}-3-bromo-1H-pyrazolo[3,4-d]pyrimidine 783-bromo-4-[4-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 793-bromo-4-[4-({4-[(phenylmethyl)oxy]phenyl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 80 3-bromo-4-[4-({3-chloro-4-[(phenylmethyl)oxy]phenyl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 814-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]methyl}-N-(3-morpholin-4-ylpropyl)benzamide 824-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]methyl}-N-[3-(methyloxy)propyl]benzamide 832-[({4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4-chlorophenyl)methyl]piperazin-2-yl}methyl)oxy]-N,N- dimethylethanamine84 3-bromo-4-[4-({4-[(4-chlorophenyl)oxy]-3-nitrophenyl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine 852-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,N-dimethylacetamide 862-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylethanamine 87N-(4-bromo-3-fluorophenyl)-N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N′-[2-(dimethylamino)ethyl]urea 882-({(R)-(4-chlorophenyl)[1-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl}oxy)-N,N-dimethylethanamine 892-{[(S)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylethanamine 903-bromo-4-(4-{(R)-(4-chlorophenyl)[(2-pyrrolidin-1-ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 911-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1-(4-chlorophenyl)-4-(dimethylamino)butan-1-ol 922-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chloro-3-fluorophenyl)methyl]oxy}-N,N-dimethylethanamine 933-bromo-4-(4-{(R)-(4-chlorophenyl)[(2-piperidin-1-ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 944-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-4-(4-chlorophenyl)-N,N-dimethylbutan-1-amine 953-bromo-4-(4-{(R)-(4-chlorophenyl)[(2-morpholin-4-ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 961-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1-(4-fluorophenyl)-N-(furan-2-ylmethyl)-N-methylmethanamine 971-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1-(4-fluorophenyl)-N-methyl-N-(pyridin-2-ylmethyl)methanamine 984-{[{[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-fluorophenyl)methyl}(methyl)amino]methyl}-N,N-dimethylaniline 99[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl](1H-indol-6-yl)methanol 1003-bromo-4-(4-{(R)-(4-chloro-3-fluorophenyl)[(2-pyrrolidin-1-ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 1013-bromo-4-{4-[(4-chlorophenyl)oxy]piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine 1022-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-diethylethanamine 1032-{[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]oxy}-5-chloro-N-(2-pyrrolidin-1-ylethyl)aniline

Table 3a Representative c-MET and/or Flt-3 Inhibitors

The Compounds in Table 3a can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 3acan be used to practice the invention.

TABLE 3a Cmpd No. Name 1N-(4-fluorophenyl)-N′-[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]propanediamide 2N-(4-fluorophenyl)-N′-[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]cyclopropane-1,1-dicarboxamide 3N-({[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]amino}carbonothioyl)-2-phenylacetamide 4N-(4-fluorophenyl)-N′-(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)cyclopropane-1,1- dicarboxamide5 2-phenyl-N-{[(4-{[1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)amino]carbonothioyl}acetamide 6N-(4-fluorophenyl)-N′-[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl]cyclopropane-1,1-dicarboxamide 72-phenyl-N-({[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl]amino}carbonothioyl)acetamide 8N-(4-fluorophenyl)-N′-(4-{[9- (tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide 92-phenyl-N-{[(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)amino]carbonothioyl}acetamide 10N-(4-fluorophenyl)-N′-[4-(9H-purin- 6-yloxy)phenyl]cyclopropane-1,1-dicarboxamide 11 2-phenyl-N-({[4-(9H-purin-6-yloxy)phenyl]amino}carbonothioyl)acetamide 12N-{3-fluoro-4-[(6-{[(2-morpholin-4-ylethyl)amino]carbonyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Table 3b Additional Representative c-MET, c-KIT, and/or Flt-3 Inhibitors

The Compounds in Table 3b can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 3bcan be used to practice the invention.

TABLE 3b Entry Name 1 N-[({3-fluoro-4-[(6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-yl)oxy]phenyl}amino)carbonothioyl]-2-phenylacetamide 2N-{[(3-fluoro-4-{[7-({[(3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-yl]oxy}phenyl)amino]carbonothioyl}-2-phenylacetamide 3N-{[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)(methyl)amino]carbonothioyl}-2-phenylacetamide 41-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)imidazolidin-2-one5 1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-(phenylmethyl)imidazolidin-2-one 61-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-(phenylacetyl)imidazolidin-2-one 7 ethyl[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)amino](oxo)acetate 8N-{[(4-{[6,7-bis(methyloxy)quinazolin-4-yl]amino}-3-fluorophenyl)amino]carbonothioyl}-2-phenylacetamide 9N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-methyl-N-(2-phenylethyl)sulfamide 10N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-(phenylmethyl)-1,2,4-oxadiazol-5-amine 111-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)piperidin-2-one 12 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(phenylmethyl)ethanediamide 13N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-4-phenyl-1,3-thiazol-2-amine 14N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide 15N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-1-phenylmethanesulfonamide 16N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-2-phenylethanesulfonamide 174-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(phenylmethyl)benzenesulfonamide 184-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N-(phenylmethyl)benzenesulfonamide 194-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(2-phenylethyl)benzenesulfonamide 204-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N-(2-phenylethyl)benzenesulfonamide 214-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(3-phenylpropyl)benzenesulfonamide 221-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)pyrrolidin-2-one 23 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl(phenylmethyl)carbamate 244-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl (2-phenylethyl)carbamate25 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N-(3-phenylpropyl)benzenesulfonamide 26N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-phenylethanediamide 27N-{[(3-fluoro-4-{[7-{[(2-methyloctahydrocyclopenta[c]pyrrol-5-yl)methyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}phenyl)amino]carbonothioyl}-2-phenylacetamide 28N-[(Z)-[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)amino](imino)methyl]-2-phenylacetamide 294-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-[2-(phenyloxy)ethyl]benzenesulfonamide 30N,N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-bis-(3-phenylpropane-1-sulfonamide) 31N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-phenylpropane-1-sulfonamide 32N2-[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)sulfonyl]-N1-phenylglycinamide 33N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-2-phenylacetamide 34N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)amino]carbonothioyl}-2-phenylacetamide 356-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3-benzothiazol-2-amine 366-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-amine 37N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2-phenylacetamide 38N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2-morpholin-4-ylethyl)ethanediamide 39benzyl-{[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester 40N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-(phenylmethyl)glycinamide 41N2-acetyl-N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-(phenylmethyl)glycinamide 42N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3-benzothiazol-2-yl)-2-phenylacetamide 43benzyl-{[6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylcarbamoyl]-methyl}-carbamic acid tert-butyl ester 44N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2-(phenylmethyl)glycinamide 45N2-acetyl-N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2-(phenylmethyl)glycinamide 46N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-3-phenylpropanamide 47N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-4-phenylbutanamide 48N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2-methyl-N2-(phenylmethyl)glycinamide 49N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-{2-[4-(methyloxy)phenyl]ethyl}ethanediamide 50N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-methyl-N2-(phenylmethyl)glycinamide 514-[(2-amino-1,3-benzothiazol-6-yl)oxy]-6,7-bis(methyloxy)-1-(2-oxo-2-phenylethyl)quinolinium 52 N-{[(4-{[6,7-bis(methyloxy)quinolin-4-yl]amino}phenyl)amino]carbonothioyl}-2-phenylacetamide 53N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-3-phenylpropanamide 54N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)amino]carbonothioyl}-2-phenylacetamide 55N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2,3-dihydro-1H-inden-1-yl)ethanediamide 56N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2,3-dihydro-1H-inden-2-yl)ethanediamide 57N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(1,2,3,4-tetrahydronaphthalen-1-yl)ethanediamide 58N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-(2-phenylethyl)-N-(phenylmethyl)sulfamide 59N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-(trifluoroacetyl)glycinamide 60N-{[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-methyl}-benzamide 61N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N′-(4-fluorophenyl)propanediamide 62N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]ethanediamide 63N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-(4-methylphenyl)ethyl]ethanediamide 64N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2-phenylpropyl)ethanediamide 65N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-(4-chlorophenyl)ethyl]ethanediamide 66N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N,N′-bis(phenylmethyl)sulfamide 67N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N,N′-bis(2-phenylethyl)sulfamide 68 ethyl[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)amino](oxo)acetate 69N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(2-phenylethyl)ethanediamide 70N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(4-fluorophenyl)propanediamide 71N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(1,2,3,4-tetrahydronaphthalen-2-yl)ethanediamide 72N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-(1-methylpyrrolidin-2-yl)ethyl]ethanediamide 73N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-(phenyloxy)ethyl]ethanediamide 74N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-hydroxy-1-(phenylmethyl)ethyl]urea 751-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-[(4-methylphenyl)sulfonyl]-4-(phenylmethyl)imidazolidin-2-one 76N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-methyl-N-(2-phenylethyl)ethanediamide 77N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-{[3-(trifluoromethyl)phenyl]methyl}ethanediamide 78N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-{2-[3-(trifluoromethyl)phenyl]ethyl}ethanediamide 79N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-3-oxo-4-phenylbutanamide 80N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-2-[3-(trifluoromethyl)phenyl]acetamide 816-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-[2-(phenyloxy)ethyl]-1,3-benzothiazol-2-amine 826-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-(2-piperidin-1-ylethyl)-1,3-benzothiazol-2-amine 836-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-methyl-N-(2-phenylethyl)-1,3-benzothiazol-2-amine 846-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-(2-pyrrolidin-1-ylethyl)-1,3-benzothiazol-2-amine 856-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-{[3-(trifluoromethyl)phenyl]methyl}-1,3-benzothiazol-2-amine 866-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-{2-[3-(trifluoromethyl)phenyl]ethyl}-1,3-benzothiazol-2-amine 87N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-[3-(trifluoromethyl)phenyl]propanediamide 88N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2-[3-(trifluoromethyl)phenyl]acetamide 89N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-{[3-(trifluoromethyl)phenyl]methyl}glycinamide 90N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-(2-phenylethyl)glycinamide 91N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-{2-[3-(trifluoromethyl)phenyl]ethyl}glycinamide 92benzyl-{[5-chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylcarbamoyl]-methyl}-carbamic acid tert-butyl ester 93N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N2-(phenylmethyl)glycinamide 94N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2-[3,5-bis(trifluoromethyl)phenyl]acetamide 95N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]acetamide 96N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(2- phenylethyl)ethanediamide97N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)ethanediamide 98N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]ethanediamide 99N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-methyl-N2-{[3-(trifluoromethyl)phenyl]methyl}glycinamide 100N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-methyl-N2-{2-[3-(trifluoromethyl)phenyl]ethyl}glycinamide 101N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-methyl-N2-(2-phenylethyl)glycinamide 1021-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-4-(phenylmethyl)imidazolidin-2-one 103N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridazin-3-yl)-N′-(4-fluorophenyl)propanediamide 104N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(2-chlorophenyl)propanediamide 105N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(3-chlorophenyl)propanediamide 106N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N2-methyl-N2-(phenylmethyl)glycinamide 107N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(4-chlorophenyl)propanediamide 108(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2-[(methyloxy)imino]propanamide 109(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2-[(ethyloxy)imino]propanamide 110(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2-{[(phenylmethyl)oxy]imino}propanamide 111N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-1-(phenylmethyl)prolinamide 1121-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-3-[(4-methylphenyl)sulfonyl]-4-(phenylmethyl)imidazolidin-2-one 1131-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4-(phenylmethyl)imidazolidin-2-one 114N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4-(phenylmethyl)-4,5-dihydro-1,3-oxazol-2-amine 1156,7-bis(methyloxy)-4-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}oxy)quinoline 1161-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4-(phenylmethyl)piperazin-2-one 117N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-(phenylmethyl)alaninamide 118N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-methyl-N2-(phenylmethyl)alaninamide 119N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-(phenylmethyl)leucinamide 120N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-methyl-N2-(phenylmethyl)leucinamide 121N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-(phenylmethyl)valinamide 1224-(6,7-dimethoxy-quinolin-4-ylamino)-N-(3-phenyl-propyl)-benzamide 1234-benzyl-1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-tetrahydro-pyrimidin-2-one 124N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 1252-(Benzyl-methyl-amino)-N-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-methyl-butyramide (note: Alphabetic order of prefixes ignored whileselecting parent chain) 126N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-2-phenoxyimino-propionamide 1272-Benzyloxyimino-N-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-2-phenyl-acetamide 1284-[4-(4-Benzyl-piperidin-1-yl)-phenoxy]-6,7-dimethoxy-quinoline 129N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2-isopropyl-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-oxalamide 130N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2-ethyl-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-oxalamide 1314-(4-{3-Chloro-5-[2-(4-fluoro-phenylcarbamoyl)-acetylamino]-pyridin-2-yloxy}-6-methoxy-quinolin-7-yloxymethyl)-piperidine-1-carboxylic acidtert-butyl ester 132N-{5-Chloro-6-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 133N-{5-Chloro-6-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 134N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-N′-phenethyl-oxalamide 135N-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 136N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 137N-{4-[7-(2-Diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-N′-phenethyl-oxalamide 138N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-methyl-N′-phenethyl-oxalamide 139N-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 140N-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 1412-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-{3-fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2-oxo- acetamide142N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2-oxo-2-(3-phenyl-pyrrolidin-1-yl)-acetamide 143N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2-oxo-2-(2-phenyl-morpholin-4-yl)-acetamide 144N-(2-Dimethylamino-2-phenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 145N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-oxo-2-phenyl-ethyl)-oxalamide 146N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-2,2-difluoro-N′-(4-fluoro-phenyl)-malonamide 147N-Benzyl-N′-{3-fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 148N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(2-fluoro-phenyl)-ethyl]-oxalamide 149N-[2-(3-Chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 150N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(2-methoxy-phenyl)-ethyl]-oxalamide 151N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-pyridin-3-yl-ethyl)-oxalamide 152N-Benzyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 153N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 154N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(2-trifluoromethyl-phenyl)-ethyl]-oxalamide 155N-[2-(2-Ethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 156N-[2-(2,4-Dimethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 157N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1S-phenyl-2-p-tolyl-ethyl)-oxalamide 158N-[2-(4-Chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 159N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamic acid 160N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(3-fluoro-phenyl)-ethyl]-oxalamide 161N-[2-(2-Chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 162N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(3-methoxy-phenyl)-ethyl]-oxalamide 163N-(1,2-Diphenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 164N-[2-(2,4-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 165N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 166N-[2-(4-Ethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 167N-[2-(4-Ethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 168N-[2-(4-Ethoxy-3-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 169N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(4-phenoxy-phenyl)-ethyl]-oxalamide 170N-[2-(3-Ethoxy-4-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 171N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-pyridin-2-yl-ethyl)-oxalamide 172N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-pyridin-4-yl-ethyl)-oxalamide 173N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(4-fluoro-phenyl)-ethyl]-oxalamide 174N-[2-(2-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 175N-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 176N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2R-phenyl-propyl)-oxalamide 177N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-indan-1-yl-oxalamide 178N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-isobutyl-oxalamide 179N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(3-methyl-butyl)-oxalamide 180N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2R-phenyl-propyl)-oxalamide 181N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-phenyl-propyl)-oxalamide 182N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-indan-2-yl-oxalamide 183N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1R-phenyl-ethyl)-oxalamide 184N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1S-phenyl-ethyl)-oxalamide 185N-[2-(3-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 186N-[2-(2,6-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 187N-[2-(2,4-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 188N-(2-Benzo[1,3]dioxol-5-yl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 189N-[2-(3-Bromo-4-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 190N-[2-(3,5-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 191N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-o-tolyl-ethyl)-oxalamide 192N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-m-tolyl-ethyl)-oxalamide 193N-[2-(3-Ethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 194N-[2-(3,4-Dimethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 195N-[2-(2,5-Dimethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 196N-[2-(3-Chloro-4-propoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 197N-[2-(4-Butoxy-3-chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 198N-[2-(4-tert-Butyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 199N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(4-sulfamoyl-phenyl)-ethyl]-oxalamide 200N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-oxalamide 201N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(3-hydroxy-4-methoxy-phenyl)-ethyl]-oxalamide 202N-(2,4-Dichloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 203N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(4-fluoro-2-trifluoromethyl-benzyl)-oxalamide 204N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1-p-tolyl-ethyl)-oxalamide 205N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(3-fluoro-4-trifluoromethyl-benzyl)-oxalamide 206N-(3-Chloro-4-fluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 207N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[1-(3-methoxy-phenyl)-ethyl]-oxalamide 208N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1-naphthalen-2-yl-ethyl)-oxalamide 209N-(4-Chloro-3-trifluoromethyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 210N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1-p-tolyl-ethyl)-oxalamide 211N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(6-trifluoromethyl-pyridin-3-ylmethyl)-oxalamide 212N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-methyl-benzyl)-oxalamide 213N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(3-methyl-benzyl)-oxalamide 214N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(4-fluoro-3-trifluoromethyl-benzyl)-oxalamide 215N-(3,5-Dichloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 216N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1R,2,3,4-tetrahydro-naphthalen-1-yl)-oxalamide 217N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1S,2,3,4-tetrahydro-naphthalen-1-yl)-oxalamide 218N-Cyclopentyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 219N-[1-(4-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 220N-(2-Fluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 221N-[2-(3,4-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 222N-(4-Fluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 223N-(2,3-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 224N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-phenoxy-ethyl)-oxalamide 225N-(2,2-Diphenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 226N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(4-methoxy-phenyl)-ethyl]-oxalamide 227N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-phenyl-propyl)-oxalamide 228N-[2-(4-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 229N-{4-[7-(1-Ethyl-piperidin-4-ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2-oxo-2-(2-phenyl-morpholin-4-yl)-acetamide 230N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(3-fluoro-5-trifluoromethyl-benzyl)-oxalamide 231N-(3,5-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 232N-(2-Chloro-5-trifluoromethyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 233N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2-dimethylamino-2-phenyl-ethyl)-oxalamide 234N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(4-methoxy-benzyl)-oxalamide 235N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(4-trifluoromethyl-benzyl)-oxalamide 236N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(3-methoxy-benzyl)-oxalamide 237N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(3-trifluoromethyl-benzyl)-oxalamide 238N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(3-trifluoromethoxy-benzyl)-oxalamide 239N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-methoxy-benzyl)-oxalamide 240N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-trifluoromethyl-benzyl)-oxalamide 241N-(3-Chloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 242N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-trifluoromethoxy-benzyl)-oxalamide 243N-(2-Chloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 244N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(4-trifluoromethoxy-benzyl)-oxalamide 245N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(4-methoxy-benzyl)-oxalamide 246N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(4-trifluoromethyl-benzyl)-oxalamide 247N-{4-[7-(Azetidin-3-ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-N′-phenethyl-oxalamide 248N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-azetidin-3-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 249N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-hydroxy-2-phenyl-ethyl)-oxalamide 250N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(2,4-difluoro-phenyl)-malonamide 251N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(4-fluoro-phenyl)-N′-methyl-malonamide 252N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1R-phenyl-propyl)-oxalamide 253N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(1R-phenyl-propyl)-oxalamide 254N-(3,4-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 255N-(2,6-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 256N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[2-(4-fluoro-phenyl)-ethyl]-oxalamide 257N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-phenyl-oxalamide 258N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(3-fluoro-phenyl)-oxalamide 259N-(4-Chloro-3-fluoro-phenyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 260N-(3,4-Dimethoxy-phenyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 261N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(3-methyl-butyl)-oxalamide 262N-(3,3-Dimethyl-butyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 263N-{5-Chloro-6-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 264N-{5-Chloro-6-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 265N-{5-Chloro-6-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide 266N-(4-Chloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 267N-(3,5-Dimethoxy-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 268N-(4-Butyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 269N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-p-tolyl-ethyl)-oxalamide 270N-(3,5-Bis-trifluoromethyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 271N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-pyrazin-2-ylmethyl-oxalamide 272N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-pyridin-2-ylmethyl-oxalamide 273N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 274N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 275N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-fluoro-3-trifluoromethyl-benzyl)-oxalamide 276N-[2-(2-Bromo-6-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 277N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N-methyl-oxalamide 278N-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 279N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-fluoro-5-trifluoromethyl-benzyl)-oxalamide 280N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-[1-(4-fluoro-phenyl)-ethyl]-oxalamide 281N-(1S-Benzyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 282N-{3-Fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide 283N-[2-(4-Amino-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 2842-(4-Benzyl-piperidin-1-yl)-N-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2-oxo-acetamide 285N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-N′-(4-fluoro-phenyl)-malonamide 286N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(3-fluoro-phenyl)-malonamide 287N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-phenyl-malonamide 288N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(4-fluoro-phenyl)-2,2-dimethyl-malonamide 289N-Ethyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 290N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-isopropyl-oxalamide 291N-Butyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 292N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-methoxy-ethyl)-oxalamide 293N-Cyclopropylmethyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide 294N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-(2-morpholin-4-yl-ethyl)-oxalamide 295N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2-oxo-2-pyrrolidin-1-yl-acetamide 296N-Ethyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N-methyl-oxalamide

Table 3c Additional Representative c-MET, c-KIT, and/or Flt-3 Inhibitors

The Compounds in Table 3c can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 3ccan be used to practice the invention.

TABLE 3c Entry Name 1N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 2N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 3N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(phenylmethyl)cyclopropane-1,1-dicarboxamide 4N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-phenylcyclopropane-1,1-dicarboxamide 5N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 6N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 7N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 8N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(2-phenylethyl)cyclopropane-1,1-dicarboxamide 9N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-methylpyridin-3-yl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 10N-{4-[(7-chloroquinolin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 11N-{4-[(7-chloroquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 12N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 13N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 14N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 15N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 16N-{5-chloro-6-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]pyridin-3-yl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 17N-[5-chloro-6-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide18 N-[5-chloro-6-({6-(methyloxy)-7-[(phenylmethyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide19N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 20N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 21N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 22N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-methylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 23N-(4-fluorophenyl)-N′-[2-methyl-6-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]cyclopropane-1,1-dicarboxamide24 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 25N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloro-2-methylpyridin-3-yl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 26N-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 27N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 28N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 29N-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 30N-{3-fluoro-4-[(6-(methyloxy)-7-(2-methyloctahydrocyclo-penta[c]pyrrol-5-ylmethoxy)quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 31 N-{3-fluoro-4-[(7-(methyloxy)-6-{[(1-methylpiperidin-4-yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 32N-[5-fluoro-2-methyl-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 33N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,3,5-trifluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 34N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-2-methylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 35N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-chloro-5-methylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 36N-(3-fluoro-4-{[6-hydroxy-7-(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 37N-(4-fluorophenyl)-N′-[2-methyl-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide 38N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 39N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 40N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 41N-(4-fluorophenyl)-N′-[4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide 42N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 43N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-chloro-5-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 44N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 45N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide 46N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 47N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 48(1S,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 49(1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 50N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 51N-(4-{[6-{[2-(diethylamino)ethyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 521,1-dimethylethyl 4-(3-{[4-[(2-fluoro-4-{[(1-{[(4-fluorophenyl)amino]carbonyl}cyclopropyl)carbonyl]amino}phenyl)oxy]-6-(methyloxy)quinolin-7-yl]oxy}propyl)piperazine-1-carboxylate 53(1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 54(1R,2R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 55N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 56N-(4-{[7-{[3-(4-acetylpiperazin-1-yl)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide57 1,1-dimethylethyl 4-(3-{[4-[(2-fluoro-4-{[((1R,2R)-1-{[(4-fluorophenyl)amino]carbonyl}-2-methylcyclopropyl)carbonyl]amino}phenyl)oxy]-6-(methyloxy)quinolin-7-yl]oxy}propyl)piperazine-1-carboxylate 58N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide 59N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)azetidine-3,3-dicarboxamide 60(1R,2S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 61(1R,2R)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 62(1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 63N-(3-fluoro-4-{[7-({3-[4-(1-methylethyl)piperazin-1-yl]propyl}oxy)-6-(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 64N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 65(1R,2R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 66(1R,2R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 67(1R,2S)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 68(1R,2S)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide69N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 70(1R,2S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 71(1R,2R,3S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 72(1R,2R,3S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 73(1R,2R,3S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 74(1R,2R,3S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 75N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 76(2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 77(2R,3R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 78N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarboxamide 79N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarboxamide 80(1R,2R,3S)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 81N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarboxamide 82(1R,2R,3S)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 83N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarboxamide 84N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarboxamide 85N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarboxamide 86N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 87N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 88N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 89(2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 90N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 91N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 92(1R,2R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 93(1R,2R)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 94(2R,3R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 95(2R,3R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 96(1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 97(2R,3R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 98N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[(4-fluorophenyl)methyl]cyclopropane-1,1-dicarboxamide 99N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(2-morpholin-4-ylethyl)cyclopropane-1,1-dicarboxamide 100N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(piperidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 101N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(pyrrolidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 102N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3-(morpholin-4-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 103N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(morpholin-4-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 104N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide 105N-[3-(aminomethyl)phenyl]-N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide 106N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3-(piperidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 107N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3-(pyrrolidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide

Table 4 Representative EGFR, ErbB2, and/or VEGFR Inhibitors

The Compounds in Table 4 can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 4can be used to practice the invention. In particular, the invention canbe practiced with one or two pharmaceutically acceptable salts of aCompound of Table 4 which salt(s) are formed with one or two acidsindependently selected from hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, acetic acid,trifluoroacetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid,3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid.

TABLE 4 Entry Name 1N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 2N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 37-({[(3aR,5r,6aS)-2-acetyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)quinazolin-4-amine 4N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-amine 5 ethyl(3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 6N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine7 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 8N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(2-methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine 9 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 10N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 11N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 12N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 13N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 14N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 15N-(3,4-dichlorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 16N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 17N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(2-(methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine 18N-(4-bromo-2,3-dichlorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 19 N-(4,5-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 20N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 21 N-(3-chloro-2,4-difluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 22 N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 23N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 24 N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 25N-(3,4-dichlorophenyl)-7-[(hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl)oxy]-6-(methyloxy)quinazolin-4-amine 26N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 27 N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 28N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 29 N-(3,4-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 30N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 31 N-(3,4-dichlorophenyl)-7-{[(3R,8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 32N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 33 N-(3,4-dichlorophenyl)-7-{[(3S,8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 34N-(3,4-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 35N-(3,4-dichlorophenyl)-7-{[(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 36N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 37N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 38N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 39N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 40N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 411,4:3,6-dianhydro-5-({[4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D-xylo-hexitol 421,4:3,6-dianhydro-5-deoxy-5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-O-methyl-D-glucitol 431,4:3,6-dianhydro-5-deoxy-5-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-O-methyl-D-xylo-hexitol 441,4:3,6-dianhydro-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D-xylo-hexitol 451,4:3,6-dianhydro-5-({[4-[(3-chloro-2,4-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D-xylo-hexitol 461,4:3,6-dianhydro-5-({[4-[(4-bromo-2,3-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D-glucitol 471,4:3,6-dianhydro-2-deoxy-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-5-O-methyl-D-threo-hexitol 481,4:3,6-dianhydro-5-deoxy-5-({[4-[(4,5-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-O-methyl-D-glucitol 49(3S,9aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one 50(3S,9aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one 51(3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one 52 (3S,8aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one 53 (3S,8aS)-3-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one 54 (3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one 55N-(3,4-dichlorophenyl)-7-({2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]ethyl}oxy)-6-(methyloxy)quinazolin-4-amine 56N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy}quinazolin-4-amine 57N-(3,4-dichlorophenyl)-7-{[2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)ethyl]oxy}-6-(methyloxy)quinazolin-4-amine 58N-(3,4-dichlorophenyl)-7-{[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 59N-(3,4-dichlorophenyl)-7-{[(3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]oxy}-6-(methyloxy)quinazolin-4-amine 60N-(3,4-dichlorophenyl)-7-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy]-6-(methyloxy)quinazolin-4-amine 611,4:3,6-dianhydro-2-O-[4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 621,4:3,6-dianhydro-2-O-[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 631,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 641,4:3,6-dianhydro-2-O-methyl-5-O-{6-(methyloxy)-4-[(2,3,4-trichlorophenyl)amino]quinazolin-7-yl}-L-iditol 651,4:3,6-dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-D-xylo-hexitol 661,4:3,6-dianhydro-2-O-[4-[(4-bromo-2,3-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 671,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-L-sorbose ethylene glycol acetal 681,4:3,6-dianhydro-2-O-[4-[(3-chloro-2,4-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 691,4:3,6-dianhydro-2-O-[4-[(4,5-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 701,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-(difluoromethyl)-L-iditol 711,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 721,4:3,6-dianhydro-2-O-[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 731,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 741,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-ethyl-L-iditol 751,4:3,6-dianhydro-2-O-[4-[(3-bromo-2-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 761,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 771,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-deoxy-D-xylo-hexitol 781,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-D-glucitol 79 methyl3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-alpha-L-idofuranoside 803,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-1,2-O-(1-methylethylidene)-beta-L-xylo-hexofuranose 811,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-deoxy-5-methylidene-D-xylo-hexitol 82methyl 3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-beta-L-idofuranoside 83N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-[(octahydro-2H-quinolizin-3-ylmethyl)oxy]quinazolin-4-amine 841,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,3,4-trifluorophenyl)amino]quinazolin-7-yl}-D-iditol 851,4:3,6-dianhydro-5-O-[4-[(2-chloro-4-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 861,4:3,6-dianhydro-5-O-[4-[(2-bromo-4-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 871,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,6-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 881,4:3,6-dianhydro-5-O-[4-[(3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 891,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[4-fluoro-3-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol 901,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,4-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 911,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,5-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 921,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,3-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 931,4:3,6-dianhydro-5-O-[4-[(5-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 941,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,5-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 951,4:3,6-dianhydro-5-O-[4-[(3-chloro-4-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 961,4:3,6-dianhydro-5-O-[4-[(4-bromo-2-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 971,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 981,4:3,6-dianhydro-5-O-[4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 991,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,4,5-trifluorophenyl)amino]quinazolin-7-yl}-D-iditol 1001,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,4,6-trifluorophenyl)amino]quinazolin-7-yl}-D-iditol 1011,4:3,6-dianhydro-5-O-[4-({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}amino)-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1021,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1031,4:3,6-dianhydro-5-O-[4-[(4-bromo-2,3-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1041,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro-5-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1051,4:3,6-dianhydro-2-deoxy-5-O-[4-[(4,5-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 1061,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,3,4-trichlorophenyl)amino]quinazolin-7-yl}-D-iditol 1071,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(3,4,5-trichlorophenyl)amino]quinazolin-7-yl}-D-iditol 1081,4:3,6-dianhydro-5-O-[4-[(4-bromo-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1091,4:3,6-dianhydro-5-O-[4-[(4-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1101,4:3,6-dianhydro-5-O-[4-[(3-chloro-2-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1111,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 1121,4:3,6-dianhydro-5-O-[4-[(2-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1131,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-[(2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-D-iditol 1141,4:3,6-dianhydro-5-O-[4-[(3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1151,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-[(4-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-D-iditol 1161,4:3,6-dianhydro-5-O-[4-[(4-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1171,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 1181,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,5-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 1191,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 1201,4:3,6-dianhydro-5-O-[4-[(2-bromo-4,6-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1211,4:3,6-dianhydro-5-O-[4-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1221,4:3,6-dianhydro-5-O-[4-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1231,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[2-fluoro-3-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol1241,4:3,6-dianhydro-5-O-[4-{[2-bromo-5-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1251,4:3,6-dianhydro-5-O-[4-{[2-bromo-4-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1261,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol1271,4:3,6-dianhydro-5-O-[4-{[3-bromo-5-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1281,4:3,6-dianhydro-5-O-[4-[(2-bromophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1291,4:3,6-dianhydro-5-O-[4-[(3-bromophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1301,4:3,6-dianhydro-5-O-[4-[(4-bromophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1311,4:3,6-dianhydro-5-O-[4-[(3-bromo-4-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1321,4:3,6-dianhydro-5-O-[4-[(5-chloro-2-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1331,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,5-dimethylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 1341,4:3,6-dianhydro-5-O-[4-{[2,5-bis(methyloxy)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1351,4:3,6-dianhydro-5-O-[4-{[5-chloro-2,4-bis(methyloxy)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1361,4:3,6-dianhydro-5-O-[4-{[4-chloro-2,5-bis(methyloxy)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 1371,4:3,6-dianhydro-5-O-[4-[(3-chloro-2,4-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol 138N-(3,4-dichlorophenyl)-7-[({5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 139N-(3,4-dichlorophenyl)-7-[({3-[(dimethylamino)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 140N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(4-methylpiperazin-1-yl)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine 141N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 142N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 143N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(morpholin-4-ylmethyl)-1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine 144N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine 145N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-2-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 146N-(3,4-dichlorophenyl)-7-[({2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 147N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(phenylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 148 1,1-dimethylethyl2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholine-4-carboxylate 149N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(morpholin-4-ylmethyl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 150N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 151N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 152N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(1,4-oxazepan-2-ylmethyl)oxy]quinazolin-4-amine 153N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-3-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 154N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 155N-(3,4-dichlorophenyl)-7-{[(4-methyl-1,4-oxazepan-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 156N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 157N-(3,4-dichlorophenyl)-7-({[5-(1,1-dimethylethyl)-1,2,4-oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 158N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-phenyl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine 1597-[(2,1,3-benzothiadiazol-4-ylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 160N-(3,4-dichlorophenyl)-7-{[(5-methylisoxazol-3-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 161N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-methyl-4-phenylisoxazol-3-yl)methyl]oxy}quinazolin-4-amine 1627-[(1,3-benzothiazol-2-ylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1637-[(2,1,3-benzoxadiazol-5-ylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 164N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(2-thienyl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 165N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(1-phenyl-1H-pyrazol-4-yl)methyl]oxy}quinazolin-4-amine 166N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine 167N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine 1687-({[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1697-({[6-bromo-2-(methyloxy)naphthalen-1-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 170N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(1,3-thiazol-4-ylmethyl)oxy]quinazolin-4-amine 1717-{[(6-chloropyridin-3-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 172N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(pyridin-4-ylmethyl)oxy]quinazolin-4-amine 173N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-methyl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine 1747-{[(6-chloro-4H-1,3-benzodioxin-8-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1757-{[(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 176N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[1-methyl-3-(trifluoromethyl)-1H-thieno[2,3-c]pyrazol-5-yl]methyl}oxy)quinazolin-4-amine 177N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-phenylisoxazol-5-yl)methyl]oxy}quinazolin-4-amine 178N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2,4,6-trimethylphenyl)methyl]oxy}quinazolin-4-amine 179N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(pyridin-3-ylmethyl)oxy]quinazolin-4-amine 180N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[4-(methyloxy)phenyl]isoxazol-5-yl}methyl)oxy]quinazolin-4-amine 181N-(3,4-dichlorophenyl)-7-({[5-[(2,4-dichlorophenyl)oxy]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 182 7-[(cyclopropylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 183N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(tetrahydrofuran-2-ylmethyl)oxy]quinazolin-4-amine 1847-(cyclopentyloxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 185 7-[(2-cyclohexylethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1867-[(cyclohexylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1877-[(cyclobutylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 188N-(3,4-dichlorophenyl)-7-{[2-(1,3-dioxolan-2-yl)ethyl]oxy}-6-(methyloxy)quinazolin-4-amine 189N-(3,4-dichlorophenyl)-7-{[2-(1,3-dioxan-2-yl)ethyl]oxy}-6-(methyloxy)quinazolin-4-amine 190N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-morpholin-4-ylethyl)oxy]quinazolin-4-amine 191N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-pyrrolidin-1-ylethyl)oxy]quinazolin-4-amine 192N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-piperidin-1-ylethyl)oxy]quinazolin-4-amine 1932-(2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}ethyl)-1H-isoindole-1,3(2H)-dione 194 methyl6-O-[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-alpha-D-glucopyranoside 195N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-morpholin-4-yl-2-oxoethyl)oxy]quinazolin-4-amine 196 1,1-dimethylethyl2-[3-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate 197 1,1-dimethylethyl4-[3-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate 198N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(4-pyrrolidin-1-ylphenyl)-1,3-thiazol-2-yl]methyl}oxy)quinazolin-4-amine 199N-(3,4-dichlorophenyl)-7-[({4-[4-(diethylamino)phenyl]-1,3-thiazol-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 2005-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,3-thiazol-4-yl]-2-hydroxybenzamide 201N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-3-yl-1,3-thiazol-2-yl)methyl]oxy}quinazolin-4-amine 202N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-2-yl-1,3-thiazol-2-yl)methyl]oxy}quinazolin-4-amine 203N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-4-yl-1,3-thiazol-2-yl)methyl]oxy}quinazolin-4-amine 204N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine 205N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-morpholin-4-yl-1,2,4-oxadiazol-5-yl)methyl]oxy}quinazolin-4-amine 206N-(3,4-dichlorophenyl)-7-({[3-(dimethylamino)-1,2,4-oxadiazol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 207N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-2-yl}methyl)oxy]quinazolin-4-amine 208N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine209N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(morpholin-4-ylmethyl)-1,3-thiazol-2-yl]methyl}oxy)quinazolin-4-amine 210N-(3,4-dichlorophenyl)-7-[({4-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 211N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-{[(phenylmethyl)oxy]methyl}-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 212N-(3,4-dichlorophenyl)-7-{[(4-ethylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 213N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-4-yl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine 214N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 215 1,1-dimethylethyl4-[5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate 217N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-piperazin-1-yl-1,2,4-oxadiazol-5-yl)methyl]oxy}quinazolin-4-amine 218N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(4-methylpiperazin-1-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine 219N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 220N-(3,4-dichlorophenyl)-7-({[3-(4-ethylpiperazin-1-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 221N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[4-(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine 222N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 2237-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 224N-(3,4-dichlorophenyl)-7-({[5-(3,5-dimethylisoxazol-4-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 2257-{[(5-chloro-1-benzothien-3-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 226N-(3,4-dichlorophenyl)-7-[({3-[4-(1,1-dimethylethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 227N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[2-(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine 228N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}oxy)quinazolin-4-amine 229N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[1-(phenylmethyl)-1H-imidazol-2-yl]methyl}oxy)quinazolin-4-amine 230N-(3,4-dichlorophenyl)-7-({[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 231N-(3,4-dichlorophenyl)-7-{[(6-fluoro-4H-1,3-benzodioxin-8-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 2327-{[(3,5-dibromophenyl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 233N-(3,4-dichlorophenyl)-7-{[(2,6-difluorophenyl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 234N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(pyridin-2-ylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine235N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 2367-({[4-chloro-2-(trifluoromethyl)quinolin-6-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 237N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(1-methylpyrrolidin-2-yl)ethyl]oxy}quinazolin-4-amine 238N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 239N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 240N-(3,4-dichlorophenyl)-7-({[2-(dimethylamino)-1,3-thiazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 241N-(3,4-dichlorophenyl)-7-{[(4-ethyl-1,4-oxazepan-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 242N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-4-yl)-1,3-thiazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 243N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(2S)-pyrrolidin-2-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine 244N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(2S)-pyrrolidin-2-yl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 245[4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,3-thiazol-2-yl]methyl benzoate 246[4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,3-thiazol-2-yl]methanol 247N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}quinazolin-4-amine248N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(4S)-1,3-thiazolidin-4-yl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 249N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-2-yl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine 250N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-2-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 251N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-3-yl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine 252N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-3-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 253N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-2-yl)-1,3-thiazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 254N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-3-yl)-1,3-thiazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 255N-(3,4-dichlorophenyl)-7-[({3-[(2S)-1-ethylpyrrolidin-2-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 256N-(3,4-dichlorophenyl)-7-[({2-[(2S)-1-ethylpyrrolidin-2-yl]-1,3-thiazol-4-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 257N-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 258N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propyl-1,4-oxazepan-2-yl)methyl]oxy}quinazolin-4-amine 2597-({[4-(cyclopropylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 260N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[2-(methyloxy)ethyl]-1,4-oxazepan-2-yl}methyl)oxy]quinazolin-4-amine 261N-(3,4-dichlorophenyl)-7-({[4-(1-methylethyl)-1,4-oxazepan-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 262N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperazin-1-yl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine 263N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-pyrrolidin-2-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 264N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 265N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(2S)-1-methylpyrrolidin-2-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine 266N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(2S)-1-methylpyrrolidin-2-yl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 267N-(3,4-dichlorophenyl)-7-({[2-(4-ethylpiperazin-1-yl)-1,3-thiazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 268N-(3,4-dichlorophenyl)-7-{[(1,4-dimethylpiperazin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 2697-{[(4-cyclopentylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 270N-(3,4-dichlorophenyl)-7-({[4-(1-methylethyl)morpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 271N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(3-phenylpropyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 272N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[2-(methyloxy)ethyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine 273 ethyl2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]propanoate 274N-(3,4-dichlorophenyl)-7-{[(4-hex-5-en-1-ylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 2752-({2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]ethyl}oxy)ethanol 276 methyl3-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]propanoate 2776-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]hexanenitrile 278N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(tetrahydro-2H-pyran-2-ylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 2794-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]butanenitrile 280N-(3,4-dichlorophenyl)-7-[({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 281 methyl5-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]pentanoate 282N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-oct-7-en-1-ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 283N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 2846-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]hexan-1-ol 2857-{[(4-acetylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 2867-({[4-(cyclopropylmethyl)morpholin-2-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 287N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-prop-2-yn-1-ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 288N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-4-ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 289N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(pyridin-2-ylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 290N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pent-2-yn-1-ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 291N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 292N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 293N-(3-chloro-4-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 2947-{[(4-butyl-1,4-oxazepan-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 295(3,4-dichlorophenyl)[7-(methyloxy)-6-({[4-(2-methylpropyl)-1,4-oxazepan-2-yl]methyl}oxy)quinazolin-4-amine 2967-{[(4-acetyl-1-ethylpiperazin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 297(3,4-dichlorophenyl)(6-(methyloxy)-7-{[(4-pentyl-1,4-oxazepan-2-yl)methyl]oxy} quinazolin-4-amine 298(3,4-dichlorophenyl)[6-(methyloxy)-7-({[4-(tetrahydro-2H-pyran-2-ylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)quinazolin-4-amine 299(3,4-dichlorophenyl)[6-(methyloxy)-7-({[4-(3-thienylmethyl)-1,4-oxazepan-2-yl]methyl}oxy) quinazolin-4-amine 300N-[4-chloro-2,5-bis(methyloxy)phenyl]-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 301N-(3-bromo-2-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 3027-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)-N-(3,4,5-trichlorophenyl)quinazolin-4-amine 303N-(3-chloro-2-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 304N-(3,4-dichlorophenyl)-7-{[(4-ethanimidoyl-1,4-oxazepan-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 305N-(4-bromo-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 306N-(5-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 307N-(4-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 308N-(2,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 309N-(2,4-dibromophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 3107-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)-N-(2,3,4-trichlorophenyl)quinazolin-4-amine 311N-(3,4-dichlorophenyl)-7-{[(1-ethyl-4-methylpiperazin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 312N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholine-4-carboximidamide 313N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 314N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(tetrahydro-2H-pyran-4-yl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 315N-(3,4-dichlorophenyl)-7-({[4-(2-ethylbutyl)morpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 3167-({[4-(cyclohexylmethyl)morpholin-2-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 3172-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]ethanol 3187-{[(4-but-2-yn-1-ylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 3197-{[(4-cyclobutylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 320N-(3,4-dichlorophenyl)-7-[({4-[2-(1,3-dioxolan-2-yl)ethyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 3217-({[4-(2-cyclohexylethyl)morpholin-2-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 322N-(3,4-dichlorophenyl)-7-[({4-[2-(1,3-dioxan-2-yl)ethyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 323N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pent-4-en-1-ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 324N-(3,4-dichlorophenyl)-7-[({4-[(2R)-2-methylbutyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 325N-(3,4-dichlorophenyl)-7-({[4-(4-fluorobutyl)morpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 3263-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]butan-2-one 3271-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]butan-2-one 328N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pentylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 329N-(3,4-dichlorophenyl)-7-{[(4-hexylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 330N-(3,4-dichlorophenyl)-7-{[(4-heptylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 331N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-octylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 332N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-phenylethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 3337-{[(4-butylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 334N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-prop-2-en-1-ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 3352-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]-1-phenylethanone 336N-(3,4-dichlorophenyl)-7-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 337N-(3,4-dichlorophenyl)-7-({[4-(3-methylbut-2-en-1-yl)morpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 3387-[({4-[(2E)-3-bromoprop-2-en-1-yl]morpholin-2-yl}methyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 3392-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]acetamide 340N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-1,4-oxazepan-2-yl}methyl)oxy]quinazolin-4-amine 341N-(3,4-dichlorophenyl)-7-({[4-(3-methylbutyl)-1,4-oxazepan-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 3427-({[4-(cyclohexylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)-4-[(3,4-dichlorophenyl)methyl]-6-(methyloxy)quinazoline 3437-({[4-(2-cyclohexylethyl)-1,4-oxazepan-2-yl]methyl}oxy)-4-[(3,4-dichlorophenyl)methyl]-6-(methyloxy)quinazoline 345N-(3,4-dichlorophenyl)-7-({[4-(2-ethylbutyl)-1,4-oxazepan-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 346N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(methylsulfonyl)-1,4-oxazepan-2-yl]methyl}oxy)quinazolin-4-amine 347N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(1-methylpiperidin-4-yl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 348N-(3-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 349N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,4-oxazepane-4-carboximidamide 350N-(3-bromo-4-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 351N-(3,4-dichlorophenyl)-7-{[(1,4-diethylpiperazin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 3524-({[4-[(4-bromo-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-N′-cyanopiperidine-1-carboximidamide 353N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(methylsulfonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 354N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(phenylmethyl)sulfonyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine 355N-(3,4-dichlorophenyl)-7-[({4-[(4-fluorophenyl)sulfonyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 356N-(3,4-dichlorophenyl)-7-({[4-(ethylsulfonyl)morpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 357N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(phenylsulfonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 3587-[({4-[(3-chloropropyl)sulfonyl]morpholin-2-yl}methyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 3597-({[4-(butylsulfonyl)morpholin-2-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 360N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(4-methylphenyl)sulfonyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine 361N-(3,4-dichlorophenyl)-7-[({4-[(3,5-dimethylisoxazol-4-yl)carbonyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine362 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-{[3-(methyloxy)phenyl]acetyl}morpholin-2-yl)methyl]oxy}quinazolin-4-amine363 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-methylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 3647-[({4-[(4-butylphenyl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 3657-[({4-[(4-chlorophenyl)acetyl]morpholin-2-yl}methyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 366N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-propylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 367N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(4-methylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 368N-(3,4-dichlorophenyl)-7-[({4-[(2,5-difluorophenyl)carbonyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 3697-({[4-(cyclopentylcarbonyl)morpholin-2-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 370N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-phenylbutanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 371N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(2,3,6-trifluorophenyl)carbonyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine372 N-(3,4-dichlorophenyl)-7-({[4-(furan-3-ylcarbonyl)morpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 373N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propanoylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 374N-(3,4-dichlorophenyl)-7-{[(4-hexanoylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 375N-(3,4-dichlorophenyl)-7-({[4-(2-ethylhexanoyl)morpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 376N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(3-phenylpropanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 377N-(3,4-dichlorophenyl)-7-({[4-(2,2-dimethylpropanoyl)morpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 378N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(naphthalen-1-ylcarbonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 3797-[({4-[(2-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 3807-[({4-[(6-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 3817-({[4-(1,3-benzodioxol-5-ylcarbonyl)morpholin-2-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 382N-(3,4-dichlorophenyl)-6-[(1-methylethyl)oxy]-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine 383N-(3,4-dichlorophenyl)-6-{[2-(methyloxy)ethyl]oxy}-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine 384N-(3,4-dichlorophenyl)-6-(ethyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine 385N-(3,4-dichlorophenyl)-6-(ethyloxy)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 386N-(4-bromo-2-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 387N-(4-chloro-3-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 388N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-N-methylmorpholine-4-carboximidamide 389N-(4-bromo-3-chlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 390N-(3,4-dichlorophenyl)-6-[(1-methylethyl)oxy]-7-{[(4-methylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 391N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-{[2-(methyloxy)ethyl]oxy}quinazolin-4-amine 392N-(4-bromo-2-chlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 3937-{[(4-acetyl-1,4-oxazepan-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 3944-[(3,4-dichlorophenyl)amino]-7-{[(4-methylmorpholin-2-yl)methyl]oxy}quinazolin-6-ol 395N-(3-bromo-4-chlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 3963-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]-3-oxopropanoic acid 397 methyl4-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]-4-oxobutanoate 398N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-3-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 399N-(3-bromo-2-chlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 400N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-N-[2-(methyloxy)ethyl]morpholine-4-carboximidamide 401N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-N-ethylmorpholine-4-carboximidamide 402[(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl](piperidin-1-yl)methylidene]cyanamide 403[(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl](pyrrolidin-1-yl)methylidene]cyanamide 404[(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl](4-methylpiperazin-1-yl)methylidene]cyanamide 405N-(3,4-dichlorophenyl)-7-{[(6-ethyl-4,6-dimethylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 406N-(4-bromo-3-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 407N-(3,4-dichlorophenyl)-7-{[(6,6-dimethylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 408N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4,6,6-trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 409N-(3,4-dichlorophenyl)-7-{[2-(5,5-dimethylmorpholin-2-yl)ethyl]oxy}-6-(methyloxy)quinazolin-4-amine 410N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(4,5,5-trimethylmorpholin-2-yl)ethyl]oxy}quinazolin-4-amine 411 1,1-dimethylethyl2-(2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}ethyl)-5,5-dimethylmorpholine-4-carboxylate 412N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4,5,5-trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 413N-(4-bromo-2,3-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 414N-(4,5-dichloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 415N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(4,6,6-trimethylmorpholin-2-yl)ethyl]oxy}quinazolin-4-amine 416N-(4-bromo-2,3-difluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 417N-(4-bromo-2,5-difluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 418N-(4-bromo-3,5-difluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 419N-(3,4-dichloro-2-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 420N-(3,4-dichlorophenyl)-7-({[(2R,5S,6S)-5,6-dimethylmorpholin-2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 421N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[(2R,5S,6S)-4,5,6-trimethylmorpholin-2-yl]methyl}oxy)quinazolin-4-amine 422N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[(2S,5S,6S)-4,5,6-trimethylmorpholin-2-yl]methyl}oxy)quinazolin-4-amine 423N-(4-bromo-3-chloro-2-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 424N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 425N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 426N-(3,4-dichloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 427N-(3-chloro-2,4-difluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 428N-(2,3-dichloro-4-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 4296-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-3,3,4-trimethylmorpholin-2-one 430N-(4-bromo-2,3-dichlorophenyl)-6-(methyloxy)-7-{[(4,5,5-trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 431N-(4-bromo-5-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5-trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 432N-(4,5-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5-trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 433N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5-trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 434N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5-trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 435N-(3-chloro-2,4-difluorophenyl)-6-(methyloxy)-7-{[(4,5,5-trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 436(6S)-6-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-4-methylpiperazin-2-one 437(6S)-6-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-4-methylpiperazin-2-one 438(6S)-6-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,4-dimethylpiperazin-2-one 439(6S)-6-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,4-dimethylpiperazin-2-one 440N-(4-bromo-3-chlorophenyl)-7-{[(3a′S,4R,6′S,6a′R)-2,2-dimethyltetrahydrospiro[1,3-dioxolane-4,3′-furo[3,2-b]furan]-6′-yl]oxy}-6-(methyloxy)quinazolin-4-amine 4411,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-[(methyloxy)methyl]-L-glucitol 442 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-(methylsulfonyl)-L-glucitol 4431,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-L-glucitol 4441,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-S-methyl-5-thio-D-iditol 4451,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-morpholin-4-yl-D-iditol 4461,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-(4-methylpiperazin-1-yl)-D-iditol447 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-pyrrolidin-1-yl-D-iditol 4482-O-acetyl-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-D-iditol 4491,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-D-iditol 4501,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-(methylsulfonyl)-D-iditol 4512-amino-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-D-iditol 4521,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-(dimethylamino)-D-iditol 4531,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-(diethylamino)-D-iditol 4541,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-piperidin-1-yl-D-iditol 4552-(acetylamino)-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-D-iditol 4561,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-(trifluoromethyl)-L-glucitol457 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-[(methylsulfonyl)amino]-D-iditol458 N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-[(1-methylpyrrolidin-3-yl)oxy]quinazolin-4-amine 459N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-[(3R)-tetrahydrofuran-3-yloxy]quinazolin-4-amine 460N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-{[(3S,4R)-4-(methyloxy)tetrahydrofuran-3-yl]oxy}quinazolin-4-amine 4611,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-(6-(methyloxy)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}quinazolin-7-yl)-D-iditol 4621,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol 4631,4:3,6-dianhydro-2-deoxy-5-O-[4-{[2,3-dichloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 4641,4:3,6-dianhydro-2-deoxy-5-O-[4-{[3,4-dichloro-2-(4-methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol 4651,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-C-(trifluoromethyl)-D-glucitol 466(3,4-dichlorophenyl)[6-(methyloxy)-7-({[4-(tetrahydrofuran-2-ylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)quinazolin-4-amine 467N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 468N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 469N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 470N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 471N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 472N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 473N-(3,4-dichlorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 474N-(3,4-dichlorophenyl)-7-[(2-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}ethyl)oxy]-6-(methyloxy)quinazolin-4-amine 475N-(3,4-dichlorophenyl)-7-({2-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]ethyl}oxy)-6-(methyloxy)quinazolin-4-amine 476N-(3,4-dichlorophenyl)-7-({[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 477N-(3,4-dichlorophenyl)-7-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-6-(methyloxy)quinazolin-4-amine 4781,4:3,6-Dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-D-glucitol 4791,4:3,6-dianhydro-5-O-{4-[(3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quin-azolin-7-yl}-2-deoxy-2-fluoro-L-iditol 4801,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-(methylsulfonyl)-D-glucitol 4811,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-D-glucitol 4821,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-S-methyl-5-thio-L-iditol 4831,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-morpholin-4-yl-L-iditol 4841,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-(4-methylpiperazin-1-yl)-L-iditol485 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-pyrrolidin-1-yl-L-iditol 4862-O-acetyl-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-L-iditol 4871,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-L-iditol 4881,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-(methylsulfonyl)-L-iditol 4892-amino-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-L-iditol 4901,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-(dimethylamino)-L-iditol 4911,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-(diethylamino)-L-iditol 4921,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-piperidin-1-yl-L-iditol 4932-(acetylamino)-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-L-iditol 4941,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-(trifluoromethyl)-D-glucitol495 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-[(methylsulfonyl)amino]-L-iditol496 1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-(6-(methyloxy)-4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}quinazolin-7-yl)-L-iditol 4971,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-L-iditol 4981,4:3,6-dianhydro-2-deoxy-5-O-[4-{[2,3-dichloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-L-iditol 4991,4:3,6-dianhydro-2-deoxy-5-O-[4-{[3,4-dichloro-2-(4-methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-L-iditol 5001,4:3,6-Dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-D-glucitol 5011,4:3,6-Dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-glucitol

Representative IGF-1R Inhibitors

The Compounds in Table 5a can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 5acan be used to practice the invention.

TABLE 5a Entry Structure  1

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Table 5b Additional Representative IGF1R Inhibitors

The Compounds in Table 5b can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 5bcan be used to practice the invention.

TABLE 5b Entry Structure Name 573

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N⁶-[3-(diethylamino)propyl]-N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}pyrimidine-2,4,6- triamine574

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N⁶-[2-(diethylamino)ethyl]-N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}pyrimidine-2,4,6- triamine575

N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N⁴-[5-(1-methylethyl)-1H-pyrazol-3-yl]-6- [(3S)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine 576

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4- diamine 577

N⁴-[3-(1-methylethyl)-1H- pyrazol-5-yl]-6-[(1-methylpyrrolidin-3-yl)oxy]-N²- [(3-phenylisoxazol-5-yl)methyl]pyrimidine-2,4- diamine 578

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-{[3-(1- methylethyl)isoxazol-5-yl]methyl}-6-[(1- methylpyrrolidin-3- yl)oxy]pyrimidine-2,4-diamine 579

N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N⁴-[3-(1-methylethyl)-1H-pyrazol-5-yl]-6- [(1-methylpyrrolidin-3-yl)oxy]pyrimidine-2,4-diamine 580

N⁴-[2-(diethylamino)ethyl]-N²- {[3-(1-methylethyl)isoxazol-5-yl]methyl}-N⁶-[5-(1- methylethyl)-1H-pyrazol-3-yl]pyrimidine-2,4,6-triamine 581

N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N⁴-[5-(1-methylethyl)-1H-pyrazol-3- yl]pyrimidine-2,4-diamine 582

N⁴-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(1-methylpiperidin-3-yl)oxy]-N²- [(3-phenylisoxazol-5-yl)methyl]pyrimidine-2,4- diamine 583

N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N⁴-[5-(1-methylethyl)-1H-pyrazol-3-yl]-6- [(1-methylpiperidin-3-yl)oxy]pyrimidine-2,4-diamine 584

N-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-2-{[(3- phenylisoxazol-5-yl)methyl]oxy}pyrimidin-4- amine 585

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N²-[(4-phenyl-1H-imidazol-2- yl)methyl]pyrimidine-2,4- diamine 586

6-{[2- (dimethylamino)ethyl]oxy}-N²- {[3-(1-methylethyl)isoxazol-5-yl]methyl}-N⁴-[5-(1- methylethyl)-1H-pyrazol-3-yl]pyrimidine-2,4-diamine 587

N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N⁴-[5-(1-methylethyl)-1H-pyrazol-3-yl]-6- [(2-morpholin-4-ylethyl)oxy]pyrimidine-2,4- diamine 588

N⁴-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(2-morpholin-4-ylethyl)oxy]-N²-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine589

N⁴-[3-(1-methylethyl)-1H- pyrazol-5-yl]-N²-[(3-phenylisoxazol-5-yl)methyl]-6- [(2-piperidin-1-ylethyl)oxy]pyrimidine-2,4- diamine 590

N⁴-[3-(diethylamino)propyl]-N²- {[3-(1-methylethyl)isoxazol-5-yl]methyl}-N⁶-[5-(1- methylethyl)-1H-pyrazol-3-yl]pyrimidine-2,4,6-triamine 591

N⁴-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(3S)-3-methylpiperazin-1-yl]-N²-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4- diamine 592

N⁴-[2-(diethylamino)ethyl]-N⁶- [5-(1-methylethyl)-1H-pyrazol-3-yl]-N²-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4,6- triamine 593

N⁴-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(1-methylpiperidin-4-yl)oxy]-N²- [(3-phenylisoxazol-5-yl)methyl]pyrimidine-2,4- diamine 594

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5-yl]methyl}-6-[(2-morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine 595

N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N⁴-[3-(1-methylethyl)-1H-pyrazol-5-yl]-6- [(2-piperidin-1-ylethyl)oxy]pyrimidine-2,4- diamine 596

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-[3-(diethylamino)propyl]-N²-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 597

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-{[3-(1- methylethyl)isoxazol-5-yl]methyl}-6-[(2-piperidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 598

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5-yl]methyl}-6-[(1- methylpiperidin-3- yl)oxy]pyrimidine-2,4-diamine 599

N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N⁴-[3-(1-methylethyl)-1H-pyrazol-5-yl]-6- [(1-methylpiperidin-4-yl)oxy]pyrimidine-2,4-diamine 600

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-methyl-N²-[(3- methylisoxazol-5-yl)methyl]pyrimidine-2,4- diamine 601

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-methylisoxazol-5-yl)methyl]-6-morpholin-4- ylpyrimidine-2,4-diamine 602

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-methylisoxazol-5-yl)methyl]-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine 603

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5-yl]methyl}-6-[(1- methylpiperidin-4- yl)oxy]pyrimidine-2,4-diamine 604

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-{[3-(4- fluorophenyl)isoxazol-5-yl]methyl}-6-morpholin-4- ylpyrimidine-2,4-diamine 605

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-{[3-(4- fluorophenyl)isoxazol-5-yl]methyl}-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine 606

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-{[3-(4- fluorophenyl)isoxazol-5-yl]methyl}-6-[(2-morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine 607

N²-{[3-(4-fluorophenyl)isoxazol- 5-yl]methyl}-N⁴-[3-(1-methylethyl)-1H-pyrazol-5-yl]-6- morpholin-4-ylpyrimidine-2,4- diamine608

N²-{[3-(4-fluorophenyl)isoxazol- 5-yl]methyl}-N⁴-[3-(1-methylethyl)-1H-pyrazol-5-yl]-6- (4-methylpiperazin-1-yl)pyrimidine-2,4-diamine 609

N²-{[3-(4-fluorophenyl)isoxazol- 5-yl]methyl}-N⁴-[3-(1-methylethyl)-1H-pyrazol-5-yl]-6- [(2-morpholin-4-ylethyl)oxy]pyrimidine-2,4- diamine 610

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N²-[(3-pyridin-3-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 611

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)-N²-[(3-pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 612

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-morpholin-4-yl-N²-[(3-pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 613

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5-yl]methyl}-6-piperazin-1- ylpyrimidine-2,4-diamine 614

6-(4-acetylpiperazin-1-yl)-N⁴-(5- cyclopropyl-1H-pyrazol-3-yl)-N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}pyrimidine-2,4- diamine 615

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5-yl]methyl}-6-[4- (methylsulfonyl)piperazin-1- yl]pyrimidine-2,4-diamine616

4-{6-[(5-cyclopropyl-1H- pyrazol-3-yl)amino]-2-({[3-(1-methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4-yl}piperazine-1-carbaldehyde 617

N⁴-(3-methyl-1H-pyrazol-5-yl)- 6-morpholin-4-yl-N²-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 618

6-(4-methylpiperazin-1-yl)-N⁴- (3-methyl-1H-pyrazol-5-yl)-N²-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 619

N⁴-(3-methyl-1H-pyrazol-5-yl)- 6-[(2-morpholin-4-ylethyl)oxy]-N²-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 620

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N²-[(3-pyridin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 621

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(3,4-difluorophenyl)isoxazol-5- yl]methyl}-6-methylpyrimidine- 2,4-diamine622

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(2,4-difluorophenyl)isoxazol-5- yl]methyl}-6-methylpyrimidine- 2,4-diamine623

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N²-[(3-pyrazin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 624

5-chloro-N⁴-(3-cyclopropyl-1H- pyrazol-5-yl)-6-morpholin-4-yl-N²-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 625

5-chloro-N⁴-(3-cyclopropyl-1H- pyrazol-5-yl)-6-(4-methylpiperazin-1-yl)-N²-[(3- phenylisoxazol-5-yl)methyl]pyrimidine-2,4- diamine 626

N²-[(3-methylisoxazol-5- yl)methyl]-6-(4-methylpiperazin-1-yl)-N⁴-(3-methyl-1H-pyrazol- 5-yl)pyrimidine-2,4-diamine 627

N²-[(3-methylisoxazol-5- yl)methyl]-N⁴-(3-methyl-1H-pyrazol-5-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine 628

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)-N²-[(3-pyrimidin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 629

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-[(3-furan-3-ylisoxazol-5-yl)methyl]-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine 630

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N⁶-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-N²- [(3-methylisoxazol-5-yl)methyl]pyrimidine-2,4,6- triamine 631

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-N²- [(3-methylisoxazol-5-yl)methyl]pyrimidine-2,4- diamine 632

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-N²- {[3-(1-methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4- diamine 633

N⁴-bicyclo[2.2.1]hept-2-yl-N⁶-(5- cyclopropyl-1H-pyrazol-3-yl)-N²-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}pyrimidine-2,4,6- triamine634

N⁴-bicyclo[2.2.1]hept-2-yl-N⁶-(5- cyclopropyl-1H-pyrazol-3-yl)-N²-[(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4,6- triamine 635

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-[(3-methylisoxazol-5-yl)methyl]-6-[(1R,4R)-5- (phenylmethyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine 636

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N-{[3-(1- methylethyl)isoxazol-5-yl]methyl}-6-[(1R,4R)-5- (phenylmethyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine 637

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-morpholin-4-yl-N²-[(3-pyrimidin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 638

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N²-[(3-pyrimidin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 639

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(5-fluoropyridin-2-yl)isoxazol-5-yl]methyl}-6- methylpyrimidine-2,4-diamine 640

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)-N²-{[3-(2-thienyl)isoxazol-5- yl]methyl}pyrimidine-2,4- diamine 641

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N²-[(3-pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 642

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-(4-methylpiperazin-1-yl)-N²-[(3-pyrimidin-5-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 643

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-morpholin-4-yl-N²-[(3-pyrimidin-5-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 644

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2-(diethylamino)ethyl]oxy}-N²-{[3- (1-methylethyl)isoxazol-5-yl]methyl}pyrimidine-2,4- diamine 645

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-{[3-(1- methylethyl)isoxazol-5-yl]methyl}-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 646

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2-(diethylamino)ethyl]oxy}-N²-[(3- methylisoxazol-5-yl)methyl]pyrimidine-2,4- diamine 647

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-N²-[(3-methylisoxazol-5-yl)methyl}-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 648

N⁴-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)-N²-{[3-(1,3-thiazol-2-yl)isoxazol- 5-yl]methyl}pyrimidine-2,4- diamine649

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-[2-(dimethylamino)ethoxy]-N²-[(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 650

6-{[2- (dimethylamino)ethyl]oxy}-N²- [(3-methylisoxazol-5-yl)methyl]-N⁴-(3-methyl-1H-pyrazol-5- yl)pyrimidine-2,4-diamine 651

6-{[2-(diethylamino)ethyl]oxy}- N²-[(3-methylisoxazol-5-yl)methyl]-N⁴-(3-methyl-1H- pyrazol-5-yl)pyrimidine-2,4- diamine 652

N²-[(3-methylisoxazol-5- yl)methyl]-N⁴-(3-methyl-1H-pyrazol-5-yl)-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine653

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-methyl-N²-[2-(3- phenylisoxazol-5-yl)ethyl]pyrimidine-2,4-diamine 654

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-methyl-N²-[1-(3- phenylisoxazol-5-yl)ethyl]pyrimidine-2,4-diamine 655

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-ethylisoxazol-5-yl)methyl]-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine 656

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-ethylisoxazol-5-yl)methyl]-6-morpholin-4- ylpyrimidine-2,4-diamine 657

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N²-[(3-ethylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine 658

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-{[2-(diethylamino)ethyl]oxy}-N²-[(3- ethylisoxazol-5-yl)methyl]pyrimidine-2,4- diamine 659

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-N²-[(3-ethylisoxazol-5-yl)methyl]-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine 660

N²-{[3-(2-aminopyrimidin-4- yl)isoxazol-5-yl]methyl}-N⁴-(3-cyclopropyl-1H-pyrazol-5-yl)-6- (4-methylpiperazin-1-yl)pyrimidine-2,4-diamine 661

N⁴-(3-cyclopropyl-1H-pyrazol-5- yl)-6-(4-ethylpiperazin-1-yl)-N²-{[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4- diamine 662

2-(1-{6-[(3-cyclopropyl-1H- pyrazol-5-yl)amino]-2-({[3-(1-methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4-yl}piperidin-4-yl)ethanol 663

2-(4-{6-[(3-cyclopropyl-1H- pyrazol-5-yl)amino]-2-({[3-(1-methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4-yl}piperazin-1-yl)ethanol

Table 6 Representative Raf Inhibitors

The Compounds in Table 6 can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 6can be used to practice the invention.

TABLE 6 Entry Name 16-(2-butyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 26-[1-hydroxy-3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 36-(1-hydroxy-2-{[4-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 46-(1-hydroxy-2-{[3-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 56-{2-[(4-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 66-(1-hydroxy-3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 76-{2-[(3-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 86-{2-[(4-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 96-[1-hydroxy-3-oxo-2-(3-phenylpropyl)-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 106-{2-[(3,4-dichlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 116-{1-hydroxy-2-[(4-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 126-{2-[(4-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 136-[1-hydroxy-2-(1-methylethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 14 methyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 156-{2-[(3,4-dimethylphenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 166-(2-{[4-chloro-3-(trifluoromethyl)phenyl]methyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 176-(2-{[4-(dimethylamino)phenyl]methyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 186-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one

TABLE 6 Entry Name 196-[2-(4-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 206-[2-(3,4-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 216-[1-hydroxy-2-(4-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 223-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-3-(methyloxy)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 233-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-2-(1-methylethyl)-3-(methyloxy)-2,3-dihydro-1H-isoindol-1-one 243-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-3-hydroxy-2-phenyl-2,3-dihydro-1H-isoindol-1-one 253-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 26 methyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1-methyl-1H-benzimidazol-2-yl}carbamate 273-(1H-benzimidazol-5-yl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 285-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-N-methyl-1H-benzimidazole-2-carboxamide 293-hydroxy-3-(2-methyl-1H-benzimidazol-5-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 307-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-3,4-dihydroquinoxalin-2(1H)-one 317-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-3,4-dihydroquinoxalin-2(1H)-one 32 1,1-dimethylethyl4-{[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-dihydro-2H-isoindol-2-yl]methyl}piperidine-1-carboxylate336-(1-hydroxy-2-{[2-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 346-{2-[(3-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 356-{2-[(2-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 366-{2-[(3-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 376-{2-[(2-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 386-{2-[(2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 396-[2-(3-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 406-[1-hydroxy-2-(3-iodophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 416-[2-(3-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 426-[1-hydroxy-2-(3-nitrophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 436-{1-hydroxy-2-[3-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 446-[1-hydroxy-2-(3-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 453-hydroxy-3-(1H-indol-5-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one46 methyl [6-(1-hydroxy-3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 476-[2-(2-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 486-{[2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one 496-{[2-(1H-benzimidazol-2-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one506-(1-hydroxy-3-oxo-2-{[2-(trifluoromethyl)phenyl]methyl}-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 516-{2-[(5-bromo-2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 526-{1-hydroxy-2-[(3-nitrophenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 536-(1-hydroxy-3-oxo-2-{[3-(trifluoromethyl)phenyl]methyl}-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 546-(2-{[2,3-bis(methyloxy)phenyl]methyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 556-{1-hydroxy-2-[(3-iodophenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 566-[1-hydroxy-3-oxo-2-({3-[(trifluoromethyl)oxy]phenyl}methyl)-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 576-(1-hydroxy-2-{[2-(methylthio)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 586-[2-(3,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 596-{1-hydroxy-2-[3-(1-methylethyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 606-(1-hydroxy-3-oxo-2-{3-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 616-{1-hydroxy-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 623-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-dihydro-2H-isoindol-2-yl]benzenesulfonamide 636-{2-[5-chloro-2-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 646-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 653-hydroxy-3-(1H-indol-6-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one666-[2-(3-fluoro-5-iodophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 676-[2-(3-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 686-[2-(3,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 696-{1-hydroxy-2-[3-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 70 ethyl3-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-dihydro-2H-isoindol-2-yl]benzoate 713-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-dihydro-2H-isoindol-2-yl]benzonitrile 726-[2-(2-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 736-[2-(3-amino-5-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 746-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 756-[2-(3-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 766-[2-(3-ethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 776-[2-(3-ethynylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 786-[1-hydroxy-2-(3-hydroxyphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 796-{1-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 806-(1-hydroxy-3-oxo-2-{3-[(phenylmethyl)oxy]phenyl}-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 813-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-dihydro-2H-isoindol-2-yl]benzamide 826-{1-hydroxy-2-[3-(hydroxymethyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one 836-[2-(2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 843-hydroxy-3-[2-(methylamino)-1H-benzimidazol-5-yl]-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 856-(2-biphenyl-3-yl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 866-(2-{3-[(dimethylamino)methyl]phenyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 876-[2-(3,5-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 886-(1-hydroxy-3-oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one 896-[2-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 906-[1-hydroxy-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one 91N-methyl-2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-N-phenylbenzamide 92 methyl{5-[1-(ethyloxy)-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 93 phenylmethyl2-[(2-{[(methyloxy)carbonyl]amino}-1H-benzimidazol-5-yl)carbonyl]benzoate 943-hydroxy-3-(1H-indazol-5-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one953-hydroxy-3-(1H-indazol-6-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one96 ethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 97 2-methylpropyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 98 methyl{5-[1-hydroxy-3-oxo-2-(2-thienylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 99 methyl{5-[1-hydroxy-3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 1003-[2-amino-1-(1,1-dimethylethyl)-1H-benzimidazol-5-yl]-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 1013-(2-amino-1H-benzimidazol-5-yl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one 102 methyl[5-(1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 103 3-(methyloxy)butyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 104 methyl(5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 105 methyl(5-{1-hydroxy-3-oxo-2-[(1S)-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 106 2-(methyloxy)ethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 107 methyl{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1-methyl-1H-benzimidazol-2-yl}carbamate 108 prop-2-yn-1-yl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 109 but-2-yn-1-yl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 110 1-methylethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 111 methyl{5-[2-(2,3-dihydro-1H-inden-2-yl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 112 methyl{5-[1-hydroxy-3-oxo-2-(pyridin-4-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 113 methyl{5-[1-hydroxy-3-oxo-2-(pyridin-3-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 114 methyl(6-{2-[(3-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 115 methyl{5-[1-hydroxy-2-(3-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 116 methyl[5-(1-hydroxy-2-{[2-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 117 methyl[5-(1-hydroxy-2-{[3-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 118 methyl[5-(1-hydroxy-2-{[4-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 119 methyl(6-{2-[(4-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 120 methyl(6-{2-[(3-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 121 methyl(5-{1-hydroxy-2-[(3-iodophenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 122 methyl(5-{2-[(3-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 123 methyl(5-{2-[(2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 124 methyl{5-[1-hydroxy-3-oxo-2-(pyridin-2-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 125 phenylmethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 126 2-fluoroethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 127 propyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 128 methyl(5-{1-hydroxy-2-[4-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 129 methyl(5-{2-[(2-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 130 methyl(5-{2-[(2-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 131 methyl(5-{1-hydroxy-2-[(3-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 132 methyl(5-{1-hydroxy-2-[(4-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 133 methyl(5-{1-hydroxy-2-[(2-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 134 methyl{5-[2-(3-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 135 methyl{5-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 136 methyl{5-[2-(3-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 137 methyl(5-{1-hydroxy-2-[3-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 138 methyl{5-[2-(4-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 139 methyl{5-[2-(4-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 140 methyl{5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 141 methyl{5-[2-(3,5-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 142 methyl{5-[2-(2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 143 methyl{5-[2-(2-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 144 methyl{5-[1-hydroxy-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 145 methyl(5-{1-hydroxy-2-[2-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 146 methyl{5-[1-hydroxy-2-(4-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 147 methyl(5-{1-hydroxy-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 148 but-2-yn-1-yl(5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 149N-ethyl-N′-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}urea 150 phenylmethyl(5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 151 methyl{6-[2-(3-amino-5-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 152 piperidin-4-ylmethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 153 methyl{5-[2-(cyclopropylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 154 methyl{5-[2-(2,2-dimethylpropyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 155 methyl{5-[2-(3,5-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 156 methyl{5-[2-(3,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 157N-ethyl-N′-(5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)urea 158N′-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-N,N-dimethylurea 159 methyl{5-[2-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 1603-(4-methylpiperazin-1-yl)propyl{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 161 methyl{5-[2-(cyclohexylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 162 methyl{5-[1-hydroxy-2-(2-methylpropyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 163 methyl{5-[1-hydroxy-3-oxo-2-(1,3-thiazol-2-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 164 methyl{5-[2-(3,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 165 methyl(5-{2-[1-(3,5-difluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 166 methyl(5-{2-[1-(3-fluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 167 methyl[5-(2-cyclohexyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 168 methyl{5-[2-(2,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 169N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-N′-(phenylmethyl)urea 170 piperidin-4-yl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 171N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-N′-methylurea 172 methyl(5-{2-[1-(2-fluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 173 methyl(5-{1-hydroxy-3-oxo-2-[1-(2-thienyl)ethyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 174 methyl(5-{2-[1-(3-chlorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 175 methyl(5-{1-hydroxy-2-[3-methyl-5-(trifluoromethyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 176N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}propanamide 177 methyl{5-[2-(3,4-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 178 methyl{5-[2-(3-ethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 179 methyl{5-[2-(3-ethynylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 180 methyl{5-[2-(4-chloro-3-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 181 methyl[5-(1-hydroxy-3-oxo-2-{1-[3-(trifluoromethyl)phenyl]ethyl}-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 182 methyl(5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylpropyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 183 methyl[5-(1-hydroxy-3-oxo-2-{2-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 184 methyl{5-[2-(2,3-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 185 cyclohexyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 186 tetrahydrofuran-2-ylmethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 187 cyclopropylmethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 188N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}morpholine-4-carboxamide 189 methyl{5-[2-(cyclopentylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 190 methyl{5-[2-(2,3-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 191 methyl{5-[2-(2,3-dihydro-1H-inden-1-yl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 192 methyl(2S)-cyclohexyl[1-hydroxy-1-(2-{[(methyloxy)carbonyl]amino}-1H-benzimidazol-5-yl)-3-oxo-1,3-dihydro-2H-isoindol-2-yl]ethanoate 193methyl{5-[2-(2,6-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 194 methyl{5-[2-(3-chloro-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 195 but-3-en-1-yl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 196 2,2,2-trifluoroethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 197 methyl{5-[2-(5-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 198 methyl(5-{2-[1-(5-chloro-2-methylphenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 199 methyl(5-{1-hydroxy-3-oxo-2-[(1S)-1-phenylpropyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 200 methyl(5-{2-[1-(3-chloro-2-methylphenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 201 methyl(5-{1-hydroxy-2-[1-(5-methyl-2-thienyl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 202 methyl(5-{2-[1-(5-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 203 methyl{5-[1-hydroxy-2-(3-iodophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 204 methyl(5-{1-hydroxy-2-[3-(1-methylethyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 205 methyl{5-[2-(furan-2-ylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 206 methyl{5-[1-hydroxy-3-oxo-2-(3-thienylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 207 methyl{5-[2-(cyclobutylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 2083,3,3-trifluoro-2-hydroxy-N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-2-(trifluoromethyl)propanamide209 methyl(5-{1-hydroxy-2-[1-(4-methyl-2-thienyl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 210 methyl(5-{2-[1-(4-bromo-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 211 methyl{5-[1-hydroxy-2-(3-{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 212tetrahydrofuran-3-ylmethyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 213N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}piperidine-1-carboxamide 214 methyl{5-[2-(3-bromo-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 215 2,3-dihydroxypropyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 216 methyl{5-[1-hydroxy-3-oxo-2-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 217 methyl(5-{2-[3-(aminocarbonyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 2184,4,4-trifluoro-3-hydroxy-N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-3-(trifluoromethyl)butanamide219 methyl(5-{1-hydroxy-2-[3-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 220 methyl(5-{1-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 221 methyl[5-(1-hydroxy-3-oxo-2-{3-[(phenylmethyl)oxy]phenyl}-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 222 methyl[5-(2-biphenyl-3-yl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 223 2,2-dimethyl-3-[(phenylmethyl)oxy]propyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate224 methyl{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 225 methyl{5-[2-(3-cyanophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 226 methyl{5-[2-(3-ethynyl-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 227 methyl{5-[2-(4-fluoro-3-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 228 methyl{6-[2-(3,4-dichloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 229[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate230 methyl{5-[2-(5-bromo-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 231 methyl(5-{2-[3-(acetylamino)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 232 methyl(5-{1-hydroxy-3-oxo-2-[3-(phenylmethyl)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 233 methyl(5-{2-[1-(4-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 234 methyl(5-{1-hydroxy-3-oxo-2-[3-(phenylcarbonyl)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 235 methyl[5-(2-{3-[(dimethylamino)methyl]phenyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 236 methyl(5-{2-[3-(aminosulfonyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 237 methyl{5-[2-(3-acetylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 238 methyl{5-[2-(3-ethyl-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 239 methyl{5-[2-(3-chloro-5-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 240N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-2-methylpropanamide 241 methyl(5-{2-[1-(3-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 242 methyl[5-(1-hydroxy-3-oxo-2-pyridin-3-yl-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 243 methyl(5-{1-hydroxy-3-oxo-2-[3-(phenylamino)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 244 methyl{5-[2-(5-bromo-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 245 methyl{5-[2-(5-chloro-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 246 methyl{5-[2-(3,5-dichloro-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 2472,2-dimethyl-3-(methyloxy)propyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 2483-hydroxy-2,2-dimethylpropyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 249 methyl(5-{2-[1-(5-bromo-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 250 methyl{5-[2-(4,5-dichloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 251 methyl{5-[2-(3-bromo-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 252 methyl{5-[2-(3-chloro-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 253N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}pent-4-ynamide 254 methyl(6-{1-methyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 255 methyl[5-(1-hydroxy-3-oxo-2-{3-[(1,1,2,2-tetrafluoroethyl)oxy]phenyl}-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 256 methyl{5-[1-hydroxy-3-oxo-2-(3-piperidin-4-ylphenyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 257 methyl{5-[2-(3-ethenylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 258 methyl(5-{2-[3-(dimethylamino)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 2592,2-difluoro-N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}cyclopropanecarboxamide 260N-ethyl-N′-{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}urea 261 methyl{5-[2-(3-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 262N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-4-[(phenylmethyl)oxy]butanamide 263N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-4-piperidin-1-ylbutanamide 264N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-4-(4-methylpiperazin-1-yl)butanamide 265N-{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}butanamide 266 methyl{6-[2-(3-bromophenyl)-5,6-dichloro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 267 methyl[5-(1-hydroxy-2-{3-[methyl(phenyl)amino]phenyl}-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 268 methyl{5-[1-hydroxy-3-oxo-2-(phenylsulfonyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 269 methyl{5-[(2-{[(phenylamino)carbonyl]amino}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 270 methyl(5-{[2-({[(phenylmethyl)oxy]carbonyl}amino)phenyl]carbonyl}-1H-benzimidazol-2-yl)carbamate 271 methyl[5-({2-[(2-phenylhydrazino)carbonyl]phenyl}carbonyl)-1H-benzimidazol-2-yl]carbamate 272 methyl{5-[(2-{[(phenyloxy)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 273 but-2-yn-1-yl{5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 274N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-3-piperidin-1-ylpropanamide 275N-{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}propanamide 276N-(4-fluorophenyl)-2-{[2-(pent-4-ynoylamino)-1H-benzimidazol-6-yl]carbonyl}benzamide 2774-(diethylamino)-N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}butanamide 278N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-4-pyrrolidin-1-ylbutanamide 2793-piperidin-1-ylpropyl{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 2803-(4-methylpiperazin-1-yl)propyl{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 281 methyl{5-[2-(3-bromophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 282 methyl{5-[2-(3-ethynyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 283 2-piperidin-1-ylethyl{5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 284 methyl{5-[2-(3-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 285 methyl{5-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 286N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-2,2-dimethyl-3-piperidin-1-ylpropanamide 287N-{5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-4-piperidin-1-ylbutanamide 288N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-4-piperidin-1-ylbutanamide 289 methyl[6-({2-[(phenylcarbonyl)amino]phenyl}carbonyl)-1H-benzimidazol-2-yl]carbamate 290 methyl{5-[1-hydroxy-2-(3-morpholin-4-ylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 291 2-(dimethylamino)ethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 2922-(diethylamino)ethyl{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 2932-piperidin-1-ylethyl{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 2943-piperidin-1-ylpropyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 2952-piperidin-1-ylethyl{6-[2-(3-bromophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 296 methyl{6-[2-(3-bromophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 2972-[methyl(phenylmethyl)amino]ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate298 methyl{5-[1-hydroxy-3-oxo-2-(3-pyrrolidin-1-ylphenyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 299 methyl{5-[2-(5-chloro-2,3-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 300 methyl{5-[1-hydroxy-3-oxo-2-(pyrrolidin-2-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 301 methyl{5-[1-hydroxy-3-oxo-2-(pyrrolidin-3-ylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 302 (1-methylpiperidin-2-yl)methyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 303[(2S)-1-methylpyrrolidin-2-yl]methyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate304 octahydro-2H-quinolizin-1-ylmethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 305methyl {5-[2-(5-bromo-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3065-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1,3-dihydro-2H-benzimidazol-2-one 307 methyl{5-[2-(3-bromo-2,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 308 2-morpholin-4-ylethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 309(1-methylpiperidin-3-yl)methyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 310methyl(5-{2-[5-chloro-2-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 311 methyl[5-(2-{3-[cyclohexyl(methyl)amino]phenyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 3128-azabicyclo[3.2.1]oct-3-ylmethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 313methyl {6-[1-(3-bromophenyl)-5-oxopyrrolidin-2-yl]-1H-benzimidazol-2-yl}carbamate 314 (1-methylpiperidin-4-yl)methyl{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3151,1-dimethylethyl4-({[({5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}amino)carbonyl]oxy}methyl)piperidine-1-carboxylate 316 (1-methylpiperidin-4-yl)methyl{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3172-(1-methylpiperidin-4-yl)ethyl{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 318methyl ({6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}amino)(oxo)acetate 319N-(5-{1-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)-4-piperidin-1-ylbutanamide 320 methyl{6-[2-(3-bromophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 321 4-(diethylamino)but-2-yn-1-yl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 322methyl{5-[2-(3-chloro-2,6-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3232-(2-oxopyrrolidin-1-yl)ethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3242-(2,5-dioxopyrrolidin-1-yl)ethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3252,2,3,3-tetrafluorocyclobutyl{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3261-acetyl-N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}piperidine-4-carboxamide 327N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}cyclobutanecarboxamide 328 methyl[5-(2-{3-[ethyl(phenyl)amino]phenyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate 329N-{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-2,2-difluorocyclopropanecarboxamide 330cyclobutyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 331 2,2-difluoroethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3322-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyridin-2-ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 333 1-methylethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 334 cyclopropylmethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 335N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}cyclopropanecarboxamide 336 2-(methyloxy)ethyl{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 337tetrahydrofuran-2-ylmethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 338N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-2-(2-thienyl)acetamide 339 methyl{6-[2-(3-chloro-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 340 ethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 341 2-fluoroethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 342 methyl(5-{1-hydroxy-3-oxo-2-[2-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 343N′-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-N,N-diethylpentanediamide 344 cyclobutylmethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3452,2,2-trifluoroethyl{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 346 methyl(5-{2-[3-(1,1-dimethylethyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 347 methyl{6-[2-(3-chloro-2-fluorophenyl)-7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3482-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(phenylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 349 methyl{6-[4,7-dichloro-2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 350phenylmethyl 2-[(2-{[(ethyloxy)carbonyl]amino}-1,3-benzoxazol-5-yl)carbonyl]benzoate 351 methyl{5-[2-(5-chloro-3-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 352 methyl{5-[2-(5-ethynyl-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 353 methyl{5-[2-(3-ethynyl-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3542-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 355 methyl{5-[2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3562-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(1,3-thiazol-2-ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 357 ethyl{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1,3-benzoxazol-2-yl}carbamate 358 methyl{5-[2-(5-chloro-3-iodo-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 359 methyl{5-[2-(3-ethyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 360 methyl{5-[2-(5-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3612-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 362 methyl{5-[2-(2-fluoro-3-iodophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 363 methyl{6-[2-(5-ethynyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3642-(3-ethynyl-2-fluorophenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 365 methyl{5-[2-(2,5-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 366 methyl{5-[2-(3-ethenyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 367 methyl(6-{2-[2-fluoro-3-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 368 methyl(5-{1-hydroxy-2-[2-methyl-5-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 369 methyl{5-[2-(3-ethynyl-2-fluorophenyl)-7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 370 methyl{5-[2-(2-fluoro-3-prop-1-yn-1-ylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 371 methyl{5-[2-(5-chloro-2-methylphenyl)-7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 372 methyl{5-[2-(3-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3733-hydroxy-2-[3-(methyloxy)phenyl]-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 3743-hydroxy-2-(3-methylphenyl)-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 3752-(5-chloro-2-methylphenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 376 methyl{6-[2-(5-chloro-2-methylphenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 377 methyl{5-[2-(3-ethynyl-2-fluorophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3782-(3-chloro-2-fluorophenyl)-3-{2-[(6-chloropyridazin-3-yl)amino]-1H-benzimidazol-5-yl}-3-hydroxy-2,3-dihydro-1H-isoindol-1-one 3792-(3-chloro-2-fluorophenyl)-4,7-difluoro-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 380 methyl{5-[2-(2-fluoro-5-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 381 methyl(5-{2-[2-fluoro-5-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 382 methyl(5-{1-hydroxy-2-[5-methyl-2-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate 383 methyl{5-[2-(3-ethynyl-5-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3842-(3-chloro-2-fluorophenyl)-3-{2-[(5-chloropyrimidin-2-yl)amino]-1H-benzimidazol-5-yl}-3-hydroxy-2,3-dihydro-1H-isoindol-1-one 3852-(3-chloro-2-fluorophenyl)-3-hydroxy-3-{2-[(4-methylpyrimidin-2-yl)amino]-1H-benzimidazol-5-yl}-2,3-dihydro-1H-isoindol-1-one 3863-(2-{[4,6-bis(methyloxy)pyrimidin-2-yl]amino}-1H-benzimidazol-5-yl)-2-(3-chloro-2-fluorophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one 3872-(3-chloro-2-fluorophenyl)-3-hydroxy-3-(2-{[4-methyl-6-(methyloxy)pyrimidin-2-yl]amino}-1H-benzimidazol-5-yl)-2,3-dihydro-1H-isoindol-1-one 3883-hydroxy-2-(3-methylphenyl)-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 3892-(5-chloro-2-methylphenyl)-3-hydroxy-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one 390 methyl{6-[2-(2-fluoro-3-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate 3913-hydroxy-2-[3-(methyloxy)phenyl]-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one 392 methyl{6-[(2-{[(2-thienylmethyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 393 methyl{6-[(2-{[(3-methylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 394 methyl{6-[(2-{[(3-bromophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 395 methyl{6-[(2-{[(3-chlorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 396 methyl{6-[(2-{[(3-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 397 methyl(6-{[2-({[3-(methyloxy)phenyl]amino}carbonyl)phenyl]carbonyl}-1H-benzimidazol-2-yl)carbamate 398 methyl(6-{[2-({[3-(trifluoromethyl)phenyl]amino}carbonyl)phenyl]carbonyl}-1H-benzimidazol-2-yl)carbamate 399 methyl{6-[(2-{[(3-ethylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 400 methyl{6-[(2-{[(3-ethynylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 401 methyl{6-[(2-{[(3-chloro-4-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 402 methyl{6-[(2-{[(5-chloro-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 403 methyl{6-[(2-{[(3-iodophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 404 methyl(6-{[2-({[3-(1-methylethyl)phenyl]amino}carbonyl)phenyl]carbonyl}-1H-benzimidazol-2-yl)carbamate 405 methyl{6-[(2-{[(3-thienylmethyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 406 methyl{6-[(2-{[(3-bromo-4-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 407 methyl{6-[(2-{[(3-chloro-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 408 methyl{6-[(2-{[(4-fluoro-3-methylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 409 methyl{6-[(2-{[(5-bromo-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 410 methyl{6-[(2-{[(5-bromo-2,4-difluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 411 methyl{6-[(2-{[(5-chloro-2,4-difluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 412 methyl{6-[(2-{[(3-bromo-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 413 methyl{6-[(2-{[(3-ethenylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 414 methyl{6-[(2-{[(3-ethynyl-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 415 methyl{6-[(2-{[(5-chloro-2-methylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 416 methyl{6-[(2-{[(5-bromo-2-methylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 417 methyl{6-[(2-{[(2-fluoro-3-iodophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 418 methyl{6-[(2-{[(3-ethenyl-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate 419 methyl{6-[(2-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-benzimidazol-2-yl}carbamate

Table 7 Representative EGFR and/or VEGFR Inhibitors

The Compounds in Table 7 can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 7can be used to practice the invention.

TABLE 7 Entry Name 1(3Z)-3-[[5-(methyloxy)-1H-benzimidazol-2-yl](phenyl)methylidene]-5-{[1-(phenylmethyl)pyrrolidin-3-yl]amino}-1,3-dihydro-2H-indol-2-one 2(3Z)-5-[(1-ethylpiperidin-3-yl)amino]-3-[[5-(methyloxy)-1H-benzimidazol-2-yl](phenyl)methylidene]-1,3-dihydro-2H-indol-2-one 3(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[5-(methyloxy)-1H-benzimidazol-2-yl](phenyl)methylidene]-1,3-dihydro-2H-indol-2-one 4(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[1H-imidazol-2-yl(phenyl)methylidene]-1,3-dihydro-2H-indol-2-one 5(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{[5-(methyloxy)-1H-benzimidazol-2-yl][4-(methyloxy)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one 6(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[5-(methyloxy)-1H-benzimidazol-2-yl](4-methylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one 7(3Z)-3-[1H-benzimidazol-2-yl(4-nitrophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 8(3Z)-3-{1H-benzimidazol-2-yl[4-(methyloxy)phenyl]methylidene}-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 9(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 10(3Z)-3-[[5-(methyloxy)-1H-benzimidazol-2-yl](phenyl)methylidene]-5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 11(3Z)-3-[(4-aminophenyl)(1H-benzimidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 12(3Z)-3-[1H-benzimidazol-2-yl(4-methylphenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 13(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[1H-imidazol-2-yl(4-methylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one 14(3Z)-5-[(1-ethylpiperidin-4-yl)oxy]-3-[[5-(methyloxy)-1H-benzimidazol-2-yl](phenyl)methylidene]-1,3-dihydro-2H-indol-2-one 15(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{1H-imidazol-2-yl[4-(methyloxy)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one 16(3Z)-3-[1H-benzimidazol-2-yl(4-fluorophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 17(3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 18(3Z)-3-[1H-benzimidazol-2-yl(3-fluorophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 19(3Z)-3-[1H-benzimidazol-2-yl(3-nitrophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 203-((Z)-1H-benzimidazol-2-yl{5-[(1-ethylpiperidin-4-yl)amino]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)benzonitrile 21(3Z)-3-[(3-aminophenyl)(1H-benzimidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 22(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-(piperidin-4-ylamino)-1,3-dihydro-2H-indol-2-one 233-((Z)-1H-benzimidazol-2-yl{5-[(1-ethylpiperidin-4-yl)amino]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)benzenecarboximidamide 24(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 25(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 26(3Z)-3-{1H-benzimidazol-2-yl[3-(methyloxy)phenyl]methylidene}-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 27(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 282-(2-{2-[(Z)-{5-[(1-ethylpiperidin-4-yl)amino]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}(phenyl)methyl]-1H-imidazol-4-yl}ethyl)-1H-isoindole-1,3(2H)-dione29 (3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-({1-[2-(dimethylamino)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 30(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-{[1-(methylsulfonyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one 31(3Z)-5-(8-azabicyclo[3.2.1]oct-3-ylamino)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-1,3-dihydro-2H-indol-2-one 32(3Z)-3-{1H-benzimidazol-2-yl[3-(methyloxy)phenyl]methylidene}-5-[(1-ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one 33(3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one 34(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-{[1-(phenylmethyl)piperidin-4-yl]oxy}-1,3-dihydro-2H-indol-2-one 35(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one 36(3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}oxy)-1,3-dihydro-2H-indol-2-one 37(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}oxy)-1,3-dihydro-2H-indol-2-one 38(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 39(3Z)-3-{1H-benzimidazol-2-yl[3-(methyloxy)phenyl]methylidene}-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 40(3Z)-3-[(3-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 41(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 42(3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 43(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)(methyl)amino]-1,3-dihydro-2H-indol-2-one 44(3Z)-3-[(3-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one 45(3Z)-3-[1H-benzimidazol-2-yl(4-chlorophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 46(3Z)-3-[1H-benzimidazol-2-yl(3-fluorophenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 47(3Z)-3-[1H-benzimidazol-2-yl(4-fluorophenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 48(3Z)-3-[(3-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 49(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 50(3Z)-3-[1H-benzimidazol-2-yl(3-fluoro-4-methylphenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 51(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 52(3Z)-3-[1H-benzimidazol-2-yl(4-fluoro-3-methylphenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 53(3Z)-3-[(3-chloro-4-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 54(3Z)-3-[(3,4-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 55(3Z)-3-[(5-chloro-1H-benzimidazol-2-yl)(phenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 56(3Z)-3-[(5-chloro-1H-benzimidazol-2-yl)(3,5-difluorophenyl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 57(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluoro-4-methylphenyl)(1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 58(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(4-fluorophenyl)(1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 59(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[1H-imidazol-2-yl(4-propylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one 60(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{1H-imidazol-2-yl[4-(trifluoromethyl)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one 61(3E)-3-[(3,5-difluorophenyl)(5-fluoro-1H-benzimidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 62(3Z)-3-[(3,5-difluorophenyl)(5-fluoro-1H-benzimidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 63(3Z)-3-[(3-fluoro-4-methylphenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 64(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(4-methyl-1H-imidazol-2-yl)(4-methylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one 65(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[3-fluoro-4-(trifluoromethyl)phenyl](1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 66(3Z)-3-[(4-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 67(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluoro-4-methylphenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 68(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{1H-imidazol-2-yl[6-(trifluoromethyl)pyridin-3-yl]methylidene}-1,3-dihydro-2H-indol-2-one 69(3Z)-3-[1H-imidazol-2-yl(4-methylphenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 70(3Z)-3-[(3-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 71(3Z)-3-{1H-imidazol-2-yl[4-(trifluoromethyl)phenyl]methylidene}-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 72(3Z)-3-[(5-chloro-1H-benzimidazol-2-yl)(phenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 73(3Z)-3-[(3,5-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 74(3Z)-3-[(3,5-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 75(3Z)-3-[(3,5-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 76(3Z)-3-[(3,5-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 77(3Z)-3-[(4-methyl-1H-imidazol-2-yl)(4-methylphenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 78(3Z)-3-[(4-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 79(3Z)-3-[(3,4-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 80(3Z)-3-[(3-chloro-4-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 81(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-(piperidin-4-ylamino)-1,3-dihydro-2H-indol-2-one 82(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(2-piperidin-1-ylethyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one 83(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(2-morpholin-4-ylethyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one 84(3Z)-5-({1-[2-(diethylamino)ethyl]piperidin-4-yl}amino)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one85(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(2-pyrrolidin-1-ylethyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one 86(3Z)-3-[1H-imidazol-2-yl(4-methylphenyl)methylidene]-5-[(1-methylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 87(3Z)-3-[(3-fluorophenyl)(1H-1,2,4-triazol-5-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 88ethyl 2-{(Z)-(3-fluorophenyl)[5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}-4-methyl-1H-imidazole-5-carboxylate 89(3Z)-3-[1H-imidazol-2-yl(phenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 90(3Z)-3-{1H-imidazol-2-yl[4-(methyloxy)phenyl]methylidene}-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 91(3Z)-3-[(4-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 92(3Z)-3-[[3-fluoro-4-(trifluoromethyl)phenyl](1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one93 (3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(methylsulfonyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one 94(3Z)-3-[1H-imidazol-2-yl(4-propylphenyl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 95(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(4-phenyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 96(3Z)-3-[(3-fluorophenyl)(4-phenyl-1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 97(3Z)-3-[(3-fluoro-4-methylphenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one98(3Z)-3-{1H-imidazol-2-yl[6-(trifluoromethyl)pyridin-3-yl]methylidene}-5-({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one 99(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(1H-1,2,4-triazol-5-yl)methylidene]-1,3-dihydro-2H-indol-2-one 100(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[2-fluoro-4-(trifluoromethyl)phenyl](1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 101(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{(4-methyl-1H-imidazol-2-yl)[4-(trifluoromethyl)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one 102(3Z)-3-[(4-chlorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 103(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[3-fluoro-4-(trifluoromethyl)phenyl](4-methyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 104(3Z)-3-[(3,4-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 105(3Z)-3-[(3-chloro-4-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 106(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(4-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 107(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(2-fluorophenyl)(1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 108(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[2-fluoro-4-(trifluoromethyl)phenyl](4-methyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one 109(3Z)-3-[(2,3-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 110(3Z)-3-[(2,3-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 111(3Z)-3-[(2,4-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 112(3Z)-3-[(2,4-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 113(3Z)-3-[(2-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 114(3Z)-3-[(3-trifluoromethylphenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 115(3Z)-3-[(3-trifluoromethylphenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 116(3Z)-3-[(2,4-dichloro-5-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one 117(3Z)-3-[(2,4-dichloro-5-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one118(3Z)-3-[(4-chloro-2-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one

Table 8 c-KIT Inhibitors

The Compounds in Table 8 can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 8can be used to practice the invention.

TABLE 8 Entry Name 1N-[5-chloro-2-(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 2N-phenyl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 3N-(2-methylphenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 4N-(2-chlorophenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 5N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 6 ethyl2-[({[3-(1H-tetrazol-1-yl)phenyl]oxy}acetyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate 7N-(3-chloro-2-methylphenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 8N-(3-fluorophenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 9N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(2H-tetrazol-5-yl)phenyl]oxy}acetamide 10N-(4-chloro-2-fluorophenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide11N-(4-bromo-3-methylphenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide12N-(4-morpholin-4-ylphenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide13N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide14N-[4-bromo-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide15N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide16N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}propanamide17 N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(5-methyl-1H-tetrazol-1-yl)phenyl]oxy}acetamide 18N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2-methyl-5-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 19N-(4-chlorophenyl)-N-methyl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide20 N-[4-chloro-2-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 21N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(2,5-dioxopyrrolidin-1-yl)phenyl]oxy}acetamide 22(2E)—N-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(1H-tetrazol-1-yl)phenyl]prop-2-enamide 23N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide24 N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(2-methyl-2H-tetrazol-5-yl)phenyl]oxy}acetamide 25N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2,4-dichloro-5-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 26N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]thio}acetamide27 N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[3-(1H-tetrazol-1-yl)phenyl]glycinamide 28N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2-(1H-tetrazol-1-yl)phenyl]oxy}acetamide29 methyl 1-{3-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl)oxy]phenyl}-1H-1,2,3-triazole-4-carboxylate 301,1-dimethylethyl {4-[({[3-(1H-tetrazol-1-yl)phenyl]oxy}acetyl)amino]phenyl}carbamate 31 1,1-dimethylethyl{4-[({[4-(1H-tetrazol-1- yl)phenyl]oxy}acetyl)amino]phenyl}carbamate 32N-{4-[(1-ethylpiperidin-4-yl)amino]phenyl}-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 33N-{4-[(1-ethylpiperidin-3-yl)amino]phenyl}-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 34N-(4-aminophenyl)-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 35N-{4-[(1-ethylpiperidin-4-yl)amino]phenyl}-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 36N-{4-[(1-ethylpiperidin-3-yl)amino]phenyl}-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 37N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-pyridin-4-ylphenyl)oxy]acetamide 38N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-methyl-N~2~-[3-(1H-tetrazol-1-yl)phenyl]glycinamide 39N-1,3-benzothiazol-2-yl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 40N-quinolin-8-yl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 41N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 42N-isoquinolin-5-yl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 43N-{3-[(phenylmethyl)oxy]phenyl}-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 44N-[5-methyl-2-(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 45N-[2,5-bis(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 46N-(6-fluoro-1,3-benzothiazol-2-yl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 47 methyl3-[({[3-(1H-tetrazol-1-yl)phenyl]oxy}acetyl)amino]benzoate 485-chloro-2-[({[3-(1H-tetrazol-1- yl)phenyl]oxy}acetyl)amino]benzamide 49N-[5-chloro-2,4-bis(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 50 N-[2-(phenyloxy)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 51N-[3-(aminosulfonyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 52N-[2-(methyloxy)-5-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 53N-(4-{[(4-methylphenyl)sulfonyl]amino}phenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 54N-(5-phenyl-1H-pyrazol-3-yl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 55N-1,3-benzothiazol-2-yl-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 56N-quinolin-8-yl-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 571,1-dimethylethyl 2-{3-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl)oxy]phenyl}-1H-pyrrole-1-carboxylate 58N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-pyrrol-2-yl)phenyl]oxy}acetamide 59N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-pyrimidin-5-ylphenyl)oxy]acetamide 60N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-1,2,3-triazol-1-yl)phenyl]oxy}acetamide 614-chloro-N-(2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}ethyl)-3-(trifluoromethyl)aniline 62N-[4-chloro-3-(trifluoromethyl)phenyl]-N-(2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}ethyl)formamide 63N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-pyridin-3-ylphenyl)oxy]acetamide 64N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-furan-3-ylphenyl)oxy]acetamide 65(2E)—N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[3-(1H-tetrazol-1-yl)phenyl]prop-2-enamide 66N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[3-(1H-tetrazol-1-yl)phenyl]propanamide 67N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[6-(1H-tetrazol-1-yl)pyrimidin-4-yl]oxy}acetamide 68N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(3,5-dimethylisoxazol-4-yl)phenyl]oxy}acetamide 69N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-quinolin-7-ylphenyl)oxy]acetamide 70N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-furan-2-ylphenyl)oxy]acetamide 71N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[3-(1H-tetrazol-1-yl)phenyl]hydrazinecarboxamide 72N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-dibenzo[b,d]furan-4-ylphenyl)oxy]acetamide 73N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(4-pyrimidin-5-ylphenyl)oxy]acetamide 74N-methyl-N-[4-(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 75N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(1H-tetrazol-1-yl)phenyl]methyl}urea 76N-[4-chloro-3-(trifluoromethyl)phenyl]-N-methyl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 77N-[4-fluoro-3-(trifluoromethyl)phenyl]-N~2~-[3-(1H-tetrazol-1-yl)phenyl]glycinamide 78N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-{[3-(pyridin-2-ylamino)phenyl]oxy}acetamide 79N-[2-fluoro-5-(trifluoromethyl)phenyl]-2-[3-(1H-tetrazol-1-yl)phenyl]hydrazinecarboxamide 80N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(4-pyridin-3-ylphenyl)oxy]acetamide 81N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-pyrimidin-5-ylphenyl)methyl]urea 82N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-pyrimidin-5-ylphenyl)methyl]urea 83N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-pyridin-3-ylphenyl)methyl]urea 84 [3-(1H-tetrazol-1-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 85N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(4-pyrimidin-5-ylphenyl)oxy]acetamide 86N~2~-[4-chloro-3-(trifluoromethyl)phenyl]-N-[3-(1H-tetrazol-1-yl)phenyl]glycinamide 872-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-N-[3-(1H-tetrazol-1-yl)phenyl]acetamide 88N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-methyl-4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 89N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-1,2,3-triazol-1-yl)phenyl]oxy}acetamide 90N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 91N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 92N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-3-(1H-tetrazol-1-yl)benzenesulfonamide 93N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-N-methyl-3-(1H-tetrazol-1-yl)benzenesulfonamide 94N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(4-pyridin-3-ylphenyl)oxy]acetamide 952-({4-[2,4-bis(methyloxy)pyrimidin-5-yl]phenyl}oxy)-N-[4-fluoro-3-(trifluoromethyl)phenyl]acetamide 962-({4-[2,4-bis(methyloxy)pyrimidin-5-yl]phenyl}oxy)-N-[4-chloro-3-(trifluoromethyl)phenyl]acetamide 97N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(4-pyridin-4-ylphenyl)oxy]acetamide 98N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[3-(methyloxy)-4-(1H-tetrazol-1-yl)phenyl]glycinamide 99N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[4-(methyloxy)-3-(1H-tetrazol-1-yl)phenyl]glycinamide 100N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[4-(1H-tetrazol-1-yl)phenyl]glycinamide 101N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2,3,5,6-tetrafluoro-4-pyrimidin-5-ylphenyl)hydrazinecarboxamide 102N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(1H-tetrazol-1-yl)phenyl]methyl}urea 103N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-pyrimidin-5-ylphenyl)hydrazinecarboxamide 104N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-pyridin-3-ylphenyl)methyl]urea 105N-[4-chloro-3-(trifluoromethyl)phenyl]-2-methyl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}propanamide 106N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}propanamide 107N-({4-[2,4-bis(methyloxy)pyrimidin-5-yl]phenyl}methyl)-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 108N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[2-(methyloxy)pyrimidin-5-yl]phenyl}methyl)urea 109N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[6-(methyloxy)pyridin-3-yl]phenyl}methyl)urea 110N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({4-[2-(methyloxy)pyrimidin-5-yl]phenyl}methyl)urea 111N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({4-[6-(methyloxy)pyridin-3-yl]phenyl}methyl)urea 112 1,1-dimethylethyl 2-{4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl)oxy]phenyl}-1H-indole-1-carboxylate 113N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-4-(1H-tetrazol-1-yl)benzenesulfonamide 114N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[3-(2H-tetrazol-5-yl)phenyl]glycinamide 115N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2,6-difluoro-4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide 116 (3-pyridin-3-ylphenyl)methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 117(3-pyrimidin-5-ylphenyl)methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 118 (3-pyridin-4-ylphenyl)methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 119N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[4-(1H-tetrazol-1-yl)phenyl]hydrazinecarboxamide 120N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-pyridin-3-ylphenyl)hydrazinecarboxamide 121 (4-pyridin-3-ylphenyl)methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 122(4-pyridin-4-ylphenyl)methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 123 (4-pyrimidin-5-ylphenyl)methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 124N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-pyridin-4-ylphenyl)methyl]urea 125N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(3-pyridin-3-ylphenyl)hydrazinecarboxamide 126N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(3-pyrimidin-5-ylphenyl)hydrazinecarboxamide 127N-[5-chloro-2,4-bis(methyloxy)phenyl]-N′-[(4-pyrimidin-5-ylphenyl)methyl]urea 128N-[5-chloro-2,4-bis(methyloxy)phenyl]-N′-[(4-pyridin-3-ylphenyl)methyl]urea 129 (4-pyrimidin-5-ylphenyl)methyl [5-chloro-2,4-bis(methyloxy)phenyl]carbamate 130 (4-pyridin-3-ylphenyl)methyl[5-chloro-2,4- bis(methyloxy)phenyl]carbamate 1311-(4-pyridin-3-ylphenyl)ethyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 132 1-(4-pyrimidin-5-ylphenyl)ethyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 133N-[5-chloro-2,4-bis(methyloxy)phenyl]-N′-[(3-pyridin-3-ylphenyl)methyl]urea 134N-[5-chloro-2,4-bis(methyloxy)phenyl]-N′-[(3-pyrimidin-5-ylphenyl)methyl]urea 135 (3-pyridin-3-ylphenyl)methyl [5-chloro-2,4-bis(methyloxy)phenyl]carbamate 136 (3-pyrimidin-5-ylphenyl)methyl[5-chloro-2,4- bis(methyloxy)phenyl]carbamate 137N-[4-chloro-3-(trifluoromethyl)phenyl]-2-methyl-2-(3-pyrimidin-5-ylphenyl)hydrazinecarboxamide 138N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[(4-pyridin-3-ylphenyl)methyl]urea 139N-{[3-(6-aminopyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 140N-{[4-(6-aminopyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 141N-{[3-(2-aminopyrimidin-5-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 142N-{[4-(2-aminopyrimidin-5-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 143N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[1-(4-pyridin-3-ylphenyl)ethyl]urea 144N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[1-(4-pyrimidin-5-ylphenyl)ethyl]urea 145N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-indol-2-yl)phenyl]oxy}acetamide 146N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(isoquinolin-7- yloxy)acetamide147 N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-pyridin-4-ylphenyl)hydrazinecarboxamide 148N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(3-pyridin-4-ylphenyl)hydrazinecarboxamide 149N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-pyridin-4-ylphenyl)methyl]urea 150N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-quinoxalin-6-ylphenyl)methyl]urea 151 methyl 3-amino-6-(3-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazine-2-carboxylate 152N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-quinoxalin-6-ylphenyl)methyl]urea 153N-{[3-(2-amino-5-methylpyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 154 methyl 3-amino-6-(4-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazine-2-carboxylate 155 [3-(1H-tetrazol-1-yl)phenyl]methyl [3-chloro-4-(methyloxy)phenyl]carbamate 156N-[3-chloro-4-(methyloxy)phenyl]-N′-{[3-(1H-tetrazol-1-yl)phenyl]methyl}urea 157N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(5-hydroxy-1H-tetrazol-yl)phenyl]oxy}acetamide 158N-{[3-(2-amino-5-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 159N-{[4-(2-amino-5-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 160N-{[3-(6-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 161N-{[4-(6-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 162N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(pyrimidin-2-yloxy)phenyl]methyl}urea 163N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-3-(1H-tetrazol-1-yl)benzamide 164 3-amino-6-(3-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-[2-(dimethylamino)ethyl]pyrazine-2-carboxamide 165N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(6-fluoropyridin-3-yl)phenyl]methyl}urea 166N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[2-(methyloxy)pyridin-3-yl]phenyl}methyl)urea 167N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(6-fluoropyridin-3-yl)phenyl]methyl}urea 168N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({4-[2-(methyloxy)pyridin-3-yl]phenyl}methyl)urea 169N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(6-methylpyridin-3-yl)phenyl]methyl}urea 170N-{[4-(2-amino-5-fluoropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 171N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(6-methylpyridin-3-yl)phenyl]methyl}urea 172N-{[4-(2-aminopyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 173N-{[3-(2-aminopyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 174 [3-(6-methylpyridin-3-yl)phenyl]methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 175[3-(2-amino-5-fluoropyridin-3-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 176[3-(2-aminopyridin-3-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 177 (3-pyrazin-2-ylphenyl)methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 178N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[6-(hydroxymethyl)pyridin-3-yl]phenyl}methyl)urea 179N-{[3-(6-acetylpyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 180N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(6-cyanopyridin-3-yl)phenyl]methyl}urea 181 1,1-dimethylethyl(3S)-3-({[3-amino-6-(3-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-2-yl]carbonyl}amino)piperidine-1-carboxylate 1823-amino-6-(3-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-[(3S)-piperidin-3-yl]pyrazine-2-carboxamide 183 1,1-dimethylethyl(3S)-3-({[3-amino-6-(4-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-2-yl]carbonyl}amino)piperidine-1-carboxylate 1843-amino-6-(4-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-[(3S)-piperidin-3-yl]pyrazine-2-carboxamide 185[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 186N-{[3-(2-amino-5-fluoropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 187[6-(1H-tetrazol-1-yl)pyridin-2-yl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 188[3-(1H-benzimidazol-2-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 189[3-(6-amino-2-methylpyridin-3-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 190N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[5-(methylthio)pyridin-3-yl]phenyl}methyl)urea 191 [4-(6-methylpyridin-3-yl)phenyl]methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 192[4-(2-amino-5-fluoropyridin-3-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 193[4-(2-aminopyridin-3-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 194 (4-pyrazin-2-ylphenyl)methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 195[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 196[4-(6-amino-2-methylpyridin-3-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 197 [3-(1H-tetrazol-1-yl)phenyl]methyl1,3-benzothiazol-2-ylcarbamate 198 [3-(1H-tetrazol-1-yl)phenyl]methyl(5-bromopyridin-2-yl)carbamate 199 (3-pyridin-3-ylphenyl)methyl(3,5-dimethylphenyl)carbamate 200 (3-pyridin-3-ylphenyl)methyl[5-chloro-2- (methyloxy)phenyl]carbamate 201[4-(1H-tetrazol-1-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 202 (3-pyrimidin-5-ylphenyl)methyl[5-chloro-2- (methyloxy)phenyl]carbamate 203(4-pyrimidin-5-ylphenyl)methyl (3,4-dimethylphenyl)carbamate 204(3-pyridin-3-ylphenyl)methyl (3,4-dimethylphenyl)carbamate 2051,1-dimethylethyl 3-({[3-amino-6-(3-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-2-yl]carbonyl}amino)piperidine-1-carboxylate 206 1,1-dimethylethyl3-({[3-amino-6-(4-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-2-yl]carbonyl}amino)piperidine-1-carboxylate 2073-amino-6-(3-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-piperidin-3-ylpyrazine-2-carboxamide 208 3-amino-6-(4-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-piperidin-3-ylpyrazine-2-carboxamide 209 1,1-dimethylethyl4-{[3-amino-6-(3-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-2-yl]carbonyl}piperazine-1-carboxylate 210 1,1-dimethylethyl4-{[3-amino-6-(4-{[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-2-yl]carbonyl}piperazine-1-carboxylate 211N-({3-[5-amino-6-(piperazin-1-ylcarbonyl)pyrazin-2-yl]phenyl}methyl)-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 212N-({4-[5-amino-6-(piperazin-1-ylcarbonyl)pyrazin-2-yl]phenyl}methyl)-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 213N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(1H-pyrazol-4-yl)phenyl]methyl}urea 214N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(1H-pyrazol-4-yl)phenyl]methyl}urea 215[3-(2-piperazin-1-ylpyrimidin-5-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 216[4-(2-piperazin-1-ylpyrimidin-5-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 217N-{[3-(2-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 218N-{[4-(2-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 219N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(2-fluoropyridin-3-yl)phenyl]methyl}urea 220N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(2-fluoropyridin-3-yl)phenyl]methyl}urea 221 [3-(1H-tetrazol-1-yl)phenyl]methyl [3-(trifluoromethyl)phenyl]carbamate 222 [3-(1H-tetrazol-1-yl)phenyl]methyl[6-(trifluoromethyl)pyridin-2- yl]carbamate 223[3-(1H-tetrazol-1-yl)phenyl]methyl [4-(trifluoromethyl)pyridin-2-yl]carbamate 224N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[5-(methylthio)pyridin-2-yl]phenyl}methyl)urea 225 [3-(2,6-dimethylpyridin-3-yl)phenyl]methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 226{3-[5-(methyloxy)pyridin-3-yl]phenyl}methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 227 2,3′-bipyridin-6-ylmethyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate 228(6-pyrimidin-5-ylpyridin-2-yl)methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 229N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-isoquinolin-4-ylphenyl)methyl]urea 230N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-isoquinolin-4-ylphenyl)methyl]urea 231 [6-(1H-tetrazol-1-yl)pyridin-2-yl]methyl[4-(trifluoromethyl)pyridin-2- yl]carbamate 232[3-(1H-pyrazol-4-yl)phenyl]methyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate 233 [4-(1H-pyrazol-4-yl)phenyl]methyl[4-chloro-3- (trifluoromethyl)phenyl]carbamate

Table 9 c-KIT and/or Flt-3 Inhibitors

The Compounds in Table 9 can be prepared as pharmaceutically acceptablesalts, solvates, hydrates, and/or isomers thereof. All such salt,solvate, hydrate, and isomer combinations of the Compounds in Table 9can be used to practice the invention.

TABLE 9 Entry Name 14-((E)-2-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}ethenyl)phenol 2N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 3N-(3-ethylphenyl)-N′-(4-{3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 4N-(4-{3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea 5N-(3-acetylphenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 6N-(3,4-dichlorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 7N-(3-bromophenyl)-N′-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 8N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 9N-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)-N′-[4-(phenyloxy)phenyl]urea 10N-(3-chlorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 11N-[3,5-bis(methyloxy)phenyl]-N′-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 12N-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)-N′-{4-[(trifluoromethyl)oxy]phenyl}urea 13N-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)-N′-[4-(trifluoromethyl)phenyl]urea 14N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 15N-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea 16N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}phenyl)urea 17N-(3,4-dimethylphenyl)-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-3-yl}phenyl)urea 18N-(4-chlorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 19N-(3,5-difluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 20N-[3-(methyloxy)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 21N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[4-(4-ethylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}phenyl)urea 22N-(3-fluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 23N-(4-fluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 24N-(3-cyanophenyl)-N′-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 25N-(3,4-difluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 26N-[3,4-bis(methyloxy)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 27N-[5-chloro-2-(methyloxy)phenyl]-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-3-yl}phenyl)urea 28N-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-3-yl}phenyl)-N′-[4-(phenyloxy)phenyl]urea 29N-(2,4-difluorophenyl)-N′-(4-{3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 30N-{4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]phenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea 31N-{4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea 32N-(2,4-difluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 33N-{4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]phenyl}-N′-phenylurea 34N-[3,5-bis(trifluoromethyl)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 35N-(2-fluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 364-((E)-2-{5-[(E)-2-phenylethenyl]-1H-pyrazol-3-yl}ethenyl)phenol 372-(methyloxy)-4-((E)-2-{5-[(E)-2-phenylethenyl]-1H-pyrazol-3-yl}ethenyl)phenol38 N-(5-fluoro-2-methylphenyl)-N′-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 39N-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)-N′-phenylurea 40N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[3-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}phenyl)urea 41N-(2,4-difluorophenyl)-N′-(4-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}phenyl)urea 42N-(2,3-dihydro-1,4-benzodioxin-6-yl)-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-3-yl}phenyl)urea 43N-[2,4-bis(methyloxy)phenyl]-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-3-yl}phenyl)urea 444-((E)-2-{3-[(E)-2-(4-fluorophenyl)ethenyl]-1H-pyrazol-5-yl}ethenyl)-2-(methyloxy)phenol 454-{(E)-2-[3-(1-benzofuran-2-yl)-1H-pyrazol-5-yl]ethenyl}phenol 46N-(4-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}phenyl)-N′-(2-phenylethyl)ethanediamide 474-{(E)-2-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]ethenyl}phenol 484-((E)-2-{3-[(E)-2-(4-chlorophenyl)ethenyl]-1H-pyrazol-5-yl}ethenyl)-2-(methyloxy)phenol 494-{(E)-2-[3-(1-benzothien-2-yl)-1H-pyrazol-5-yl]ethenyl}phenol 50N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[4-(3-phenyl-1H-pyrazol-5-yl)phenyl]urea 514-((E)-2-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}ethenyl)phenol52 1,1-dimethylethyl {4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]phenyl}carbamate 53N-(5-fluoro-2-methylphenyl)-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-3-yl}phenyl)urea 544-[(E)-2-(3-phenyl-1H-pyrazol-5-yl)ethenyl]phenol 552-(methyloxy)-4-[(E)-2-(5-phenyl-1H-pyrazol-3-yl)ethenyl]phenol 564-[(E)-2-(5-naphthalen-2-yl-1H-pyrazol-3-yl)ethenyl]phenol 574-{(E)-2-[5-(2-fluorophenyl)-1H-pyrazol-3-yl]ethenyl}phenol 584-((E)-2-{3-[3-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}ethenyl)phenol594-((E)-2-{3-[(E)-2-(2,4-difluorophenyl)ethenyl]-1H-pyrazol-5-yl}ethenyl)-2-(methyloxy)phenol 604-{(E)-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]ethenyl}phenol 614-{(E)-2-[3-(4-chlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol 624-[(E)-2-(5-pyridin-2-yl-1H-pyrazol-3-yl)ethenyl]phenol 634-{(E)-2-[3-(5-chloro-1-benzofuran-2-yl)-1H-pyrazol-5-yl]ethenyl}phenol64N-(1,1-dimethylethyl)-N′-(4-{3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea 654-[(E)-2-(3-pyridin-4-yl-1H-pyrazol-5-yl)ethenyl]phenol 664-{(E)-2-[3-(3-chlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol 674-((E)-2-{5-[2-(methyloxy)phenyl]-1H-pyrazol-3-yl}ethenyl)phenol 684-{(E)-2-[3-(2-chlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol 694-[(E)-2-(3-pyridin-3-yl-1H-pyrazol-5-yl)ethenyl]phenol 704-((E)-2-{5-[3-(methyloxy)phenyl]-1H-pyrazol-3-yl}ethenyl)phenol 711,1-dimethylethyl(4-{3-[(E)-2-phenylethenyl]-1H-pyrazol-5-yl}phenyl)carbamate 724-{(E)-2-[3-(3,4-dichlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol 732-{5-[(E)-2-phenylethenyl]-1H-pyrazol-3-yl}-1-benzofuran-6-ol 744-{(E)-2-[5-(3-fluorophenyl)-1H-pyrazol-3-yl]ethenyl}phenol 752-(5-phenyl-1H-pyrazol-3-yl)-1H-benzimidazole 76N-phenyl-N′-[4-(3-phenyl-1H-pyrazol-5-yl)phenyl]urea 774-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]aniline 784-[(E)-2-(5-biphenyl-3-yl-1H-pyrazol-3-yl)ethenyl]phenol 794-((E)-2-{5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-3-yl}ethenyl)phenol

General Administration

In one aspect, the invention provides pharmaceutical compositionscomprising an inhibitor of PI3K according to the invention and apharmaceutically acceptable carrier, excipient, or diluent. In certainother specific embodiments, administration is by the oral route.Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, specifically in unit dosage forms suitable for simpleadministration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include carriers and adjuvants, etc.

Adjuvants include preserving, wetting, suspending, sweetening,flavoring, perfuming, emulsifying, and dispensing agents. Prevention ofthe action of microorganisms can be ensured by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, and the like. It may also be desirable to include isotonic agents,for example sugars, sodium chloride, and the like. Prolonged absorptionof the injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules) and the bioavailability of the drugsubstance. Recently, pharmaceutical formulations have been developedespecially for drugs that show poor bioavailability based upon theprinciple that bioavailability can be increased by increasing thesurface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in thesize range from 10 to 1,000 nm in which the active material is supportedon a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684describes the production of a pharmaceutical formulation in which thedrug substance is pulverized to nanoparticles (average particle size of400 nm) in the presence of a surface modifier and then dispersed in aliquid medium to give a pharmaceutical formulation that exhibitsremarkably high bioavailability.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One specific route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (1) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of the invention, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts or solvates, are administered in a therapeutically effectiveamount which will vary depending upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of the compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular disease-states, and the hostundergoing therapy. The compounds of the present invention can beadministered to a patient at dosage levels in the range of about 0.1 toabout 1,000 mg per day. For a normal human adult having a body weight ofabout 70 kilograms, a dosage in the range of about 0.01 to about 100 mgper kilogram of body weight per day is an example. The specific dosageused, however, can vary. For example, the dosage can depend on a numberof factors including the requirements of the patient, the severity ofthe condition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to one of ordinary skill in the art.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described above andthe other pharmaceutically active agents within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agents when acombination formulation is inappropriate.

Representative pharmaceutical formulations containing a compound ofFormula I are described below in the Pharmaceutical CompositionExamples.

Utility

Certain compounds of Formula I have been tested using the assaydescribed in Biological Example 1 and have been determined to be PI3Kinhibitors. As such compounds of Formula I are useful for treatingdiseases, particularly cancer in which PI3K activity contributes to thepathology and/or symptomatology of the disease. For example, cancer inwhich PI3K activity contributes to its pathology and/or symptomatologyinclude breast cancer, colon cancer, rectal cancer, endometrial cancer,gastric carcinoma, glioblastoma, hepatocellular carcinoma, small celllung cancer, non-small cell lung cancer, melanoma, ovarian cancer,pancreatic cancer, prostate carcinoma, acute myelogenous leukemia (AML),chronic myelogenous leukemia (CML), and thyroid carcinoma, and the like.

Suitable in vitro assays for measuring PI3K activity and the inhibitionthereof by compounds are known. Typically, the assay will measurePI3K-induced ATP consumption. For further details of an in vitro assayfor measuring PI3K activity see Biological Examples, Example 1 infra.Cellular activity can be determined using assays as described inBiological Examples 2, 3, and 4 infra. Suitable in vivo models of cancerare known to those of ordinary skill in the art. For further details ofin vivo assays see Biological Examples 5-10, infra. Examples describingthe administration of a Compound of Formula I in combination withanticancer agents are described in Biological Examples 11-14, infra.Following the examples disclosed herein, as well as that disclosed inthe art, a person of ordinary skill in the art can determine whatcombinations of a Compound of Formula I and anti-cancer agents would beeffective for treating cancer.

General Synthesis

Compounds of this invention can be made by the synthetic proceduresdescribed below. The starting materials and reagents used in preparingthese compounds are either available from commercial suppliers such asAldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), orare prepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and Supplementals (ElsevierScience Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wileyand Sons, 1991), March's Advanced Organic Chemistry, (John Wiley andSons, 4^(th) Edition) and Larock's Comprehensive Organic Transformations(VCH Publishers Inc., 1989). These schemes are merely illustrative ofsome methods by which the compounds of this invention can besynthesized, and various modifications to these schemes can be made andwill be suggested to one skilled in the art having referred to thisdisclosure. The starting materials and the intermediates of the reactionmay be isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure and over a temperature range from about−78° C. to about 150° C., in another embodiment from about 0° C. toabout 125° C. and in another embodiment at about room (or ambient)temperature, e.g., about 20° C. Unless otherwise stated (as in the caseof an hydrogenation), all reactions are performed under an atmosphere ofnitrogen.

Prodrugs can be prepared by techniques known to one skilled in the art.These techniques generally modify appropriate functional groups in agiven compound. These modified functional groups regenerate originalfunctional groups by routine manipulation or in vivo. Amides and estersof the compounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms or quaternized nitrogen atoms intheir structure. Compounds of Formula I that may be prepared through thesyntheses described herein may exist as single stereoisomers, racemates,and as mixtures of enantiomers and diastereomers. The compounds may alsoexist as geometric isomers. All such single stereoisomers, racemates andmixtures thereof, and geometric isomers are intended to be within thescope of this invention. Some of the compounds of the invention mayexist as tautomers. For example, where a ketone or aldehyde is present,the molecule may exist in the enol form; where an amide is present, themolecule may exist as the imidic acid; and where an enamine is present,the molecule may exist as an imine. All such tautomers are within thescope of the invention. In particular, imidazol-5-yl and pyrazol-5-yleach can also exist in their respective tautomeric forms imidazol-4-yland pyrazol-3-yl. Regardless of which structure or which terminology isused, each tautomer is included within the scope of the Invention.

The present invention also includes N-oxide derivatives and protectedderivatives of compounds of Formula I. For example, when compounds ofFormula I contain an oxidizable nitrogen atom, the nitrogen atom can beconverted to an N-oxide by methods well known in the art. When compoundsof Formula I contain groups such as hydroxy, carboxy, thiol or any groupcontaining a nitrogen atom(s), these groups can be protected with asuitable “protecting group” or “protective group”. A comprehensive listof suitable protective groups can be found in T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc. 1991, thedisclosure of which is incorporated herein by reference in its entirety.The protected derivatives of compounds of Formula I can be prepared bymethods well known in the art.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R- andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, selective reaction of one enantiomer withan enantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may, be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The chemistry for the preparation of the compounds of this invention isknown to those skilled in the art. In fact, there may be more than oneprocess to prepare the compounds of the invention. For specificexamples, see M. Barvian et al. J. Med. Chem. 2000, 43, 4606-4616; S. N.VanderWei et al. J. Med. Chem. 2005, 48, 2371-2387; P. L. Toogood et al.J. Med. Chem. 2005, 48, 2388-2406; J. Kasparec et al. TetrahedronLetters 2003, 44, 4567-4570; and references cited therein. See also U.S.Pre-grant publication US2004/0009993 A1 (M. Angiolini et al.), which isincorporated herein by reference, and references cited therein. Thefollowing examples illustrate but do not limit the invention. Allreferences cited herein are incorporated by reference in their entirety.

A compound of the invention where R¹ is optionally substituted alkyl, R²is hydrogen or optionally substituted alkyl, R⁴ is methyl or ethyl, R⁶is phenyl or heteroaryl each of which is optionally substituted with 1,2, 3, 4, or 5 R⁹ groups (as defined in the Summary of the Invention),and R² is hydrogen can be prepared according to Scheme 1.

To a solution of commercially available 2-methyl-2-thiopseudoureasulfate in a solvent such as water is added a base such as sodiumcarbonate and an intermediate of formula 10 at room temperature. Thereaction mixture is stirred for overnight or less. After neutralizing,11 is collected through filtration and followed by drying under vacuum.11 is then treated with POCl₃ and the reaction is heated to reflux forapproximately 2 h and then concentrated under vacuum to dryness. 1 canbe used directly in the next reaction without further purification.

An intermediate of formula 2 is prepared by reacting an intermediate offormula 1 with a primary amine R¹NH₂ in a solvent such as water and withheating. 2 is then treated with iodine monochloride in a solvent such asmethanol at around 0° C. and allowed to react for approximatelyovernight or less as needed for the reaction to go to completion to form3. After completion the residue is triturated with acetone. Theintermediate 3 is then reacted in a solvent, such as DMA, with ethylacrylate in the presence of a base, such as triethylamine, and in thepresence of a catalyst, such as Pd(OAc)₂, and (+)BINAP. The reaction isheated to approximately 100° C. and allowed to react for approximatelyovernight or less as needed for the reaction to go to completion to form4. 4 is then optionally purified by column chromatography.

5 is prepared by treating 4 with DBU in the presence of a base such asDIPEA at room temperature. Then the reaction mixture is heated to refluxand reacted for approximately 15 h. After evaporation of solvent, theresidue is triturated with acetone and collected by filtration to yield5.

6 is prepared by reacting 5 with a brominating agent such as Br₂ in asolvent such as DCM at room temperature. Then the reaction mixture isstirred for approximately overnight. The resulting product is filteredand then suspended in a solvent such as DCM and treated with a base suchas triethylamine. The mixture is then washed with water and dried over adrying agent such as Na₂SO₄ to yield 6.

A Suzuki coupling is then performed using 6 reacting with a boronic acid(or ester) of formula R⁶B(OH)₂ in a solvent such as a DME-H₂O mixture,in the presence of a catalyst such as Pd(dpppf) and a base such astriethylamine at room temperature. The reaction mixture is heated toreflux for approximately 4 h. After cooling to room temperature, thereaction mixture is partitioned with water and ethyl acetate. Afterseparation, the organic layer is dried over a drying agent such asNa₂SO₄ to yield 7.

The methylthio group of 7 is then oxidized with m-CPBA in a solvent suchas DCM at room temperature allowing to stir for approximately 4 h. Afterremoval of the solvent under reduced pressure, the product is treatedwith an amine of formula R²NH₂ in a solvent such as dioxane and stirredat room temperature for approximately overnight to yield a Compound ofFormula I.

Alternatively, a compound of the invention where R′ is optionallysubstituted alkyl, R⁴ is methyl or ethyl, R⁶ is phenyl or heteroaryleach of which is optionally substituted with 1, 2, 3, 4, or 5 R⁹ groups(as defined in the Summary of the Invention), and R² is hydrogen can beprepared according to Scheme 2.

An intermediate of formula 9 is prepared by reacting an intermediate offormula 8 with neat POCl₃ and heating. 9 is then treated with a primaryamine R¹NH₂ in a solvent such as water or THF and triethylamine at 0° C.to form 10. After removal of the solvent under reduced pressure, theintermediate 10 is then reacted with lithium aluminum hydride in asolvent such as THF at 0° C. After quenching and aqueous workup, solventremoval provided crystalline 11 without further purification. Treatmentof 11 with manganese (II) dioxide in a solvent such as methylenechloride or chloroform at room temperature provided aldehyde 12 uponfiltration and solvent removal. A Wittig reaction with aldehyde 12 canbe employed with (carbethoxymethylene)triphenylphosphorane in refluxingTHF to provide the common intermediate 4. 4 can then be used to preparea Compound of Formula I using the procedures described in Scheme 1.

A compound of the invention where R¹ is optionally substituted alkyl, R⁴is methyl or ethyl, R⁶ is phenyl or heteroaryl each of which isoptionally substituted with 1, 2, 3, 4, or 5 R⁹ groups (as defined inthe Summary of the Invention), and R² is hydrogen can be preparedaccording to Scheme 3.

An intermediate of formula 14 is prepared by reacting an intermediate offormula 13 with a primary amine R¹NH₂ in a solvent such as water andwith heating. 14 is then treated with iodine monochloride in a solventsuch as methanol at around 0° C. and allowed to react for approximatelyovernight or less as needed for the reaction to go to completion to form15. After completion the residue is triturated with acetone. Theintermediate 15 is then reacted in a solvent, such as DMA, with ethylacrylate in the presence of a base, such as triethylamine, and in thepresence of a catalyst, such as Pd(OAc)₂, and (+)BINAP. The reaction isheated to approximately 100° C. and allowed to react for approximatelyovernight or less as needed for the reaction to go to completion to form16. 16 is then optionally purified by column chromatography. A Compoundof Formula I can then be prepared from 16 by using the same reactionconditions as described in Scheme 1 (starting at the point of thepreparation of 5 from 4).

A compound of the invention where R′ is optionally substituted alkyl, R⁴is methyl or ethyl, R⁶ is phenyl or heteroaryl each of which isoptionally substituted with 1, 2, 3, 4, or 5 R⁹ groups (as defined inthe Summary of the Invention), and R² is hydrogen can alternatively beprepared according to Scheme 4.

An intermediate of formula 20 is prepared by reacting an intermediate offormula 19 with neat POCl₃ and heating. 20 is then treated with aprimary amine R¹NH₂ in a solvent such as water or THF and triethylamineat 0° C. to form 21. After removal of the solvent under reducedpressure, the intermediate 21 is then reacted with lithium aluminumhydride in a solvent such as THF at 0° C. After quenching and aqueousworkup, solvent removal provided crystalline 22 without furtherpurification. Treatment of 22 with manganese (II) dioxide in a solventsuch as methylene chloride or chloroform at room temperature providedaldehyde 23 upon filtration and solvent removal. A Knovenegal-typecondensation with 23 and an arylacetonitrile in the presence of a basesuch as potassium carbonate or sodium hydroxide in a protic solventprovides the cyclized imine 24. Acetylation of the imine with aceticanhydride is required prior to hydrolysis which takes place in thepresence of aqueous acid and heating to afford 25. Subsequently, 25 canbe oxidized to the corresponding sulfone with m-CPBA at room temperatureand displaced with ammonium to provide I.

SYNTHETIC EXAMPLES Example 12-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of 2-methyl-2-thiopseudourea sulfate (Aldrich, 58.74 g,0.422 mol) in water (1000 mL) were added sodium carbonate (81.44 g,0.768 mol) and ethyl acetoacetate (50 g, 0.384 mol) at room temperature.The reaction mixture was stirred overnight. After neutralizing to pH=8,the solid was collected through filtration followed by drying undervacuum overnight to afford 6-methyl-2-(methylthio)pyrimidin-4(3H)-one(57.2 g, 95% yield) of product. ¹H NMR (400 MHz, DMSO-d6): δ 12.47 (bs,1H), 5.96 (bs, 1H), 2.47 (s, 3H), 2.17 (s, 3H).

To the round bottom flask containing6-methyl-2-(methylthio)pyrimidin-4(3H)-one (19 g, 121.6 mmol) was addedPOCl₃ (30 mL). The reaction mixture was heated to reflux for 2 h andthen concentrated on a rotary evaporator to dryness. The crude4-chloro-6-methyl-2-(methylthio)pyrimidine was used directly in the nextreaction without further purification.

To the 4-chloro-6-methyl-2-(methylthio)pyrimidine from above was added30 mL of a solution of 70% ethylamine in water. The reaction mixture washeated to 50° C. for 3 h. After completion, excess ethylamine wasevaporated on rotary evaporator under vacuum. The solid was filtered anddried under vacuum to affordN-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 90% yield).

To the solution of N-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20g, 121.6 mmol) in methanol was added iodine monochloride (26.58 g, 163.7mmol) in small portions at 0° C. Then the reaction mixture was stirredovernight. After evaporation of solvent, the residue was triturated withacetone. The productN-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimidin-4-amine (25.2 g, 75%yield) was collected by filtration. ¹H NMR (400 MHz, CDCl₃): δ 5.37 (bs,1H), 3.52 (q, J=7.2 Hz, 1H), 2.50 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).

To the solution ofN-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimidin-4-amine (25.2 g, 81.48mmol) in DMA (260 mL) were added ethyl acrylate (12.23 g, 122.2 mmol),Pd(OAc)₂ (3.65 g, 16.25 mmol), (+)BINAP and triethyl amine (24.68 g,244.4 mmol). Then the reaction mixture was heated to 100° C. and reactedovernight. After evaporation of solvent, the residue was diluted withwater and the aqueous layer was extracted with ethyl acetate. Theproduct(E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate(16.8 g, 73% yield) was isolated by silica gel column chromatographywith 6-8% ethyl acetate in hexane as eluent. ¹H NMR (400 MHz, CDCl₃): δ7.65 (d, J=16.4 Hz, 1H), 6.20 (d, J=16.4 Hz, 1H), 5.15 (bs, 1H), 4.28(q, J=7.2 Hz, 2H), 3.54 (q, J=7.2 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H),1.35 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).

To a solution of(E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate(16.8 g, 59.8 mmol) in DIPEA was added1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.21 g, 119.6 mmol) at roomtemperature. Then the reaction mixture was heated to reflux and reactedfor 15 h. After evaporation of solvent, the residue was triturated withacetone. The product8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10.77g, 77% yield) was collected by filtration. NMR (400 MHz, CDCl₃): δ 7.78(d, J=9.6 Hz, 1H), 6.63 (d, J=9.6 Hz, 1H), 4.5 (q, J=7.2 Hz, 2H), 2.67(s, 3H), 2.62 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).

To a solution of8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.31 g,26.84 mmol) in DCM was added Br₂ (4.79 g, 29.52 mmol) dropwise at roomtemperature. Then the reaction mixture was stirred at room temperatureovernight. After filtration the solid was suspended in DCM (100 mL), andtriethylamine (20 mL) was added. The mixture was washed with water anddried with Na₂SO₄, and the product6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(6.96 g, 83% yield) was obtained after evaporation of DCM. ¹H NMR (400MHz, CDCl₃): δ 8.22 (s, 1H), 4.56 (q, J=7.2 Hz, 2H), 2.68 (s, 3H), 2.62(s, 3H), 1.34 (t, J=7.2 Hz, 3H).

To a solution of6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(0.765 g, 2.43 mmol) in DME-H₂O (10:1 11 mL) was added1H-pyrazol-5-ylboronic acid (Frontier, 0.408 g, 3.65 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withCH₂Cl₂ (Pd(dpppf), 0.198 g, 0.243 mmol) and triethylamine (0.736 g, 7.29mmol) at room temperature. Then the reaction mixture was heated toreflux and reacted for 4 h. After cooling down to room temperature, thereaction mixture was partitioned with water and ethyl acetate. Afterseparation, the organic layer was dried with Na₂SO₄, and the product8-ethyl-4-methyl-2-(methylthio)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.567 g, 77% yield) was obtained by silica gel column chromatography.¹H NMR (400 MHz, CDCl₃): δ 13.3 (bs, 1H), 8.54 (s, 1H), 7.82-7.07 (m,2H), 4.45 (q, J=7.2 Hz, 2H), 2.71 (s, 3H), 2.60 (s, 3H), 1.26 (t, J=7.2Hz, 3H).

To the solution of8-ethyl-4-methyl-2-(methylthio)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.123 g, 0.41 mmol) in DCM (2 mL) was added MCPBA (0.176 g, 77%, 0.785mmol) in a small portion at room temperature. Then the reaction mixturewas stirred for 4 h. After evaporation of DCM, dioxane (1 mL) and liquidammonia (1 mL) were introduced. The reaction was stirred at roomtemperature overnight. The product2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(50.4 mg) was obtained by silica gel column chromatography. ¹H NMR (400MHz, CD₃OD): δ 8.41 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 6.96 (d, J=2.0 Hz,1H), 4.51 (q, J=7.2 Hz, 2H), 2.64 (s, 3H), 1.29 (t, J=7.2 Hz, 3H); MS(EI) for C₁₃H₁₄N₆O: 271.3 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 1a

2-(amino)-8-ethyl-4-ethyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-D6): δ 8.40 (s, 1H), 7.27 (bs, 1H), 7.00 (s, 1H),4.40 (q, J=7.2 Hz, 2H), 2.95 (d, J=7.20 Hz, 2H), 1.14 (t, J=7.2 Hz, 3H),1.08 (t, J=7.2 Hz, 3H), 0.89 (m, 1H), 0.24 (m, 2H), 0.01 (m, 2H); MS(EI) for C₁₄H₁₆N₆O: 285.2 (MH⁺).

Example 1b

8-ethyl-4-methyl-2-(methylamino)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CH₃OH-d₄): δ 8.39 (s, 1H), 7.60 (bs, 1H), 6.93 (bs,1H), 4.53 (bs, 2H), 3.02 (s, 3H), 2.84 (bs, 3H), 1.33 (bs, 3H); MS (EI)for C₁₄H₁₆N₆O: 285.3 (MH⁺).

Example 1c

8-Ethyl-2-[(2-fluoroethyl)amino]-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CH₃OH-d₄): δ 8.34 (bs, 1H), 7.25 (bs, 1H), 6.90 (bs,1H), 4.60 (dt, J=5.2, 2.2 Hz, 2H), 4.49 (q, J=7.20 Hz, 2H), 3.78 (dt,J=5.2, 2.2 Hz, 2H), 2.64 (s, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (EI) forC₁₅H₁₇FN₆O: 317.3 (MH⁺).

Example 1d

2-Amino-8-cyclopentyl-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 13.10 (s, 1H), 8.42 (d, 1H), 7.70 (s, 1H),7.20 (bs, 2H), 6.01 (m, 1H), 2.61 (s, 3H), 2.30 (m, 2H), 2.10 (m, 2H),1.80 (m, 2H), 1.60 (m, 2H); MS (EI) for C₁₆H₁₈N₆O: 311.8 (M+H).

Intermediate 1 Alternate route to(E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate

N,N-Dimethyl acetamide dimethyl acetal (75 g, 0.56 mole) was added to asuspension of thiourea (33.0 g, 0.43 mole) in methylene chloride. Themixture was heated under reflux for 4 h. The solvent was removed and theresidue was crystallized from 5% MeOH and diethyl ether affording(1E)-N′-(aminocarbonothioyl)-N,N-dimethylethanimidamide (47.8 g, 76%yield).

A suspension of (1E)-N′-(aminocarbonothioyl)-N,N-dimethylethanimidamide(47.8 g, 0.33 mole) in methyl iodide (150 mL) and THF (350 mL) wasstirred for 18 h at room temperature. The mixture was evaporated underreduced pressure. After addition of 5% MeOH and diethyl ether, thecompound precipitated and was collected by filtration affording(1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogeniodide salt (91.0 g, 96% yield).

To a solution of(1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogeniodide salt (73.0 g, 0.26 mole) in dry dichloromethane (900 mL), wasadded ethyl 3-chloro-3-oxopropanoate (44 mL, 95% Lancaster, 0.34 mole)was added under a nitrogen atmosphere. The mixture was stirred for 4 hat room temperature, cooled to 0° C. then triethylamine (107 mL, 0.78mole) was added. The reaction mixture was stirred overnight. The solventwas removed and H₂O was added. The pH was adjusted to pH=5.0 with aceticacid and extracted with ethylacetate then evaporated and crystallizedfrom the appropriate solvent (Ethylacetate-Hexanes mixture solvent,approximately 20% ethylacetate-Hexanes). This afforded ethyl4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (36.5g, 62% yield) after drying under vacuum.

A solution of ethyl4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (60 g,0.26 mole) and phosphorous oxychloride (POCl₃, 320 mL) was heated underreflux for 4 to 5 h (monitor reaction by TLC using 30% ethylacetate andhexanes). After completion of reaction, phosphorous oxychloride wasremoved on a rotary evaporator. The residue was poured on to ice waterand extracted with ethylacetate several times. The combined organiclayers were evaporated, on a rotary evaporator, to give crude ethyl4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g). Thiscompound was used without purification.

To a solution of ethyl4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g) in THF(1000 mL) and triethylamine (110 mL, 0.81 mole) was added ethylamine(2.0 M in THF, 0.81 mole) at 0° C. This reaction mixture was stirred atroom temperature overnight and then solvents were removed on a rotaryevaporator. H₂O was added and the mixture extracted with ethyl acetateseveral times. Solvents from the combined organic layers were removed ona rotary evaporator affording 58 g (86% yield) of ethyl4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate. Thismaterial was used as such without further purification.

To a lithium aluminum hydride solution (LAH, 1.0 M solution in THF,Aldrich, 450 mL) was added a solution of ethyl4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (57 g) inTHF (1000 mL). The reaction mixture was stirred overnight. After coolingto 0° C., the reaction mixture was cautiously quenched with a 1:9mixture of H₂O/THF until gas evolution has ceased, then diluted with H₂O(500 mL) and stirred well for 2 h. The resulting slurry was extractedwith ethylacetate several times. The aqueous layer was then filteredthrough Celite and washed with ethylacetate again. The combined organiclayers were washed with brine, dried and concentrated under reducedpressure to give 41.0 g (85% yield) of[4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]methanol as alight yellow crystal, which was used without purification in the nextstep.

To a solution of[4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]methanol (41.0 g)in chloroform (4000 mL) was added manganese oxide (125 g, 1.4 mole) andstirred for 4 h at room temperature. More manganese oxide was addeduntil the disappearance of alcohol compound was observed. The reactionmixture was filtered through Celite and washed with some chloroform andevaporated all organic solvents to give 38 g (92% yield) of4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde as acolorless solid, which was used without purification in the next step.

To a solution of4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (38 g,180 mmol) in THF (500 mL) was added (Carbethoxymethylene)triphenylphosphorane (95%, Aldrich, 85.18 g, 244 mmol). The reactionmixture was heated to reflux for 1.5 h and was monitored by TLC (4:1hexanes/ethylacetate). The reaction was cooled to room temperature andwas concentrated on a rotary evaporator. It was directly subjected tocolumn chromatography (4:1 hexanes/ethylacetate) to give(E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylateas a white crystal, 46.14 g (91% yield).

Example 22-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-c]pyrimidin-7(8H)-one

To a 3-necked 3-L flask, that was equipped with an overhead stirrer, wasadded in order 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 100 g,0.696 mol, 1 equiv.), ethylamine (70% ethylamine in water, Lancaster,625 mL), 625 mL H₂O, and 125 mL TEA (0.889 mol, 1.28 equiv.). Themixture was stirred and heated at reflux for 20 h, during which time thereaction turned homogeneous. The reaction was allowed to cool to roomtemperature. The volatile ethylamine was removed on a rotary evaporator.A precipitate formed. The aqueous mixture containing the precipitate wasallowed to stand at room temperature for 2 h and then filtered. Afterdrying under vacuum, 106 g (100% yield) of2-amino-6-ethylaminopyrimidine was obtained as a colorless solid. Thismaterial was used as such in the following reaction.

To a solution of 2-amino-6-ethylaminopyrimidine (98 g, 0.64 mol) inmethanol (1.6 L) was added IC1 (115.0 g, 0.71 mol) in a small portion at15° C. Then the reaction mixture was stirred at room temperature for 3 h(monitored by LC/MS). After evaporation of solvent by rotary evaporator,the residue was triturated with acetone.2-amino-6-ethylamino-4-iodopyrimidine hydrochloride (188.5 g, 93%isolated yield) was obtained by vacuum filtration and drying. ¹H NMR(400 MHz, CD₃OD) δ 3.58 (q, 2H), 2.14 (s, 3H), 1.11 (t, 3H); MS (EI) forC₇H₁₁N₄CII: 279.1 (MH⁺).

To a three-neck round bottom flask equipped with over-head mechanicstirrer were added 2-amino-6-ethylamino-4-iodopyrimidine hydrochloride(188.5 g, 0.60 mol), ethyl acrylate (221 mL, 2.0 mol), triethylamine(285 mL, 2.0 mol), DMF (1.3 L), andtetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄, 31.3 g, 0.027 mol).The reaction mixture was heated to 95° C. and stirred for 3 h (monitoredby LC/MC). After reaction completion, the reaction mixture wasevaporated about to 1/10 of original volume and partitioned with 500 mLof ethyl acetate and 1000 mL of water. The aqueous layer was extractedwith ethyl acetate 5 times. (E)-Ethyl3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (100 g, 67%yield) was obtained by recrystallization from acetone after evaporationof ethyl acetate. ¹H NMR (400 MHz, CD₃OD) δ 7.48 (dd, J1=16.0 Hz, J2=4.0Hz, 1H), 6.20 (dd, J1=16 Hz, J2=4 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.51(q, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.3 (t, J=7.2 Hz, 3H), 1.2 (t, J=7.6Hz, 3H). MS (EI) for C₁₂H₁₈N₄O₂: 251.3 (MH⁺).

(E)-Ethyl 3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate(4.50 g, 18.0 mmol) was added to DBU (10.95 g, 4.0 equiv.) and themixture was heated to 165° C. and stirred for 24 h. After that, themixture was cooled to 70° C. followed by the addition of H₂O (20 mL) toprecipitate crystal and stirred for 1 h at room temperature. The crystalwas collected and washed with H₂O and acetone and dried under vacuum toafford 2.70 g (73.5% yield of2-amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a lightyellowish brown solid. LC/MS: Calculated for C₁₀H₁₂N₄O (204.2). Found:205.31 (M+1); HPLC analytical purity: 98.5%. ¹H NMR (400 MHz, DMSO-d₆):δ 7.9 (d, 1H), 7.20 (bs, 2H), 6.20 (m, 1H), 4.20 (q, 2H), 2.50 (s, 3H),1.20 (t, 3H); MS (EI) for C₁₀H₁₂N₄O: 205.11 (MH⁺).

2-Amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.70 g, 13.2mmol) was added to dichloromethane (100 mL), and then bromine (0.75 mL,1.10 equiv.) was added slowly. This reaction mixture was stirred for 3 hat room temperature. After that, the solvent was evaporated nearly 80%volume of reaction mixture under vacuum, and then acetone was added togive 3.54 g2-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as atan solid. LC/MS: Calculated for C₁₀H₁₁BrN₄O (283.12). Found: 285.15(M+2). HPLC analytical purity: 97.7%.

Example 32-Amino-4-methyl-8-(methylethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a crude solution ofN-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (44.6 g, 224 mmol),prepared using analogous procedures as described in Example 1, in 400 mLof methanol was added IC1 (40.0 g, 246 mmol) in small portions at roomtemperature. The reaction mixture was then stirred at for 3 h monitoringby LC/MS. After evaporation of solvent by rotary evaporator, the residuewas triturated with acetone to yield5-iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine. NMR (400MHz, CDCl₃) δ 6.37 (br m, 1H), 4.47 (m, 1H), 2.78 (s, 3H), 2.67 (s, 3H),1.41 (d, J=6.4, 6H).

5-Iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (8.1 g, 26.2mmol), ethyl acrylate (5.24 g, 52.4 mmol), triethylamine (10.6 g, 105mmol), palladium (II) acetate (1.17 g, 5.23 mmol), and tri-o-tolylphosphine (1.59 g, 5.23 mmol) were added in that order to 10.8 mL of DMAin a pressure tube and sealed. The reaction mixture was heated to 100°C. and allowed to stir overnight. The reaction was quenched byfiltration through a short silica plug washing with ACN. The solvent wasevaporated and diluted with ethyl acetate then extracted with 10° A)aqueous LiCl, followed by water and brine. NOTE: Extraction is necessaryto remove all DMA giving resolution in chromatography. The sample waspurified by silica gel column chromatography using 20% ethylacetate/hexane as eluent. Desired fractions were combined and reduced toafford 2.5 g (34% yield) of ethyl(2E)-3-[4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]acrylateas a yellow/orange oil.

(E)-Ethyl3-(4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate(2.5 g, 8.46 mmol) was dissolved in acetic acid by gentle warming.Sample was placed in microwave reactor for 6 h at 180° C., 300 W, and200 PSI. The product was purified by silica gel column chromatographyeluting with 20% ethyl acetate/hexane. Desired fractions were combinedand reduced into8-isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as ayellow powder (1.20 g, 57% yield) which was then dried under heavyvacuum overnight. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=9.6, 1H), 6.58(d, J=9.6, 1H), 5.84 (br s, 1H), 2.65 (s, 3H), 2.63 (s, 3H), 1.63 (d,J=6.8, 6H).

8-Isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(5.38 g, 21.59 mmol) was dissolved in 100 mL DCM. To the stirringsolution, m-CPBA (13.97 g, 64.78 mmol) was added. The reaction wasallowed to stir for 2.5 h at room temperature. LCMS indicated reactionhad gone to completion. Sample was diluted with 300 mL of DCM and 300 mLK₂CO₃, upon addition of base a white precipitate formed that dissolvedin excess H₂O. Organic layer was extracted further with H₂O and brine,and then dried over Na₂CO₃. The solvent was evaporated to afford theproduct8-isopropyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(6.0 g, 99% yield) as a light yellow oil that was used immediately inthe next reaction.

8-isopropyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(approximately 3.0 g) was dissolved in 50 mL THF, in a 350 mL pressuretube. While stirring, NH₃ (g) was bubbled in through solution for 1.5minutes. A color change was observed form light yellow to olive green inabout 120 seconds. The tube was sealed and stirred at room temperatureovernight. A precipitate had formed. The reaction mixture, includingprecipitate, was reduced to near dryness, filtered and washed with aminimal volume of cold THF, affording 2.88 g of2-amino-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

To a solution of2-amino-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.88 g,13.19 mmol) dissolved in 80 mL of DCM at 0° C., (4.21 g, 26.39 mmol)bromine was added. Reaction vessel was removed from ice bath and allowedto react at room temperature over night. LCMS indicated completeconversion of starting material to product. Sample was evaporated toremove DCM and excess bromine. Orange solid was diluted in ethyl acetateand extracted with 10% NaHSO₃, H₂O, and brine. Organic layer was driedover Na₂SO₄, filtered, and reduced to dryness yielding2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one asa light yellow powder (2.2 g, 56% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.08(s, 1H), 5.83 (m, 1H), 5.69 (br s, 2H), 2.60 (s, 3H), 1.58 (d, J=6.8,6H).

In a 350 mL pressure tube2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(1.50 g, 5.05 mmol), 1H-pyrazol-3-yl boronic acid (1.12 g, 10.09 mmol),K₂CO₃ (336 mg, 15.1 mmol), and tetrakis(triphenylphosphine) palladium(0) (583 mg, 0.0504 mmol) were dissolved in 50 mL dioxane and 5 mL H₂O.The tube was sealed, heated to 100° C. and allowed to react overnight. Acolor change was observed. LCMS indicated no presence of startingmaterial. Sample was filtered through a syringe filter and evaporated todryness. Compound was dissolved in ethyl acetate and triturated inhexane. Light yellow powder of2-amino-8-isopropyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(195 mg, 13.7% yield) was found to be 98% pure by HPLC. NMR (400 MHz,CDCl₃) δ 12.97 (br s, 1H), 8.35 (s, 1H), 7.60 (br s, 1H), 7.21 (s, 2H),6.94 (s, 1H), 5.86 (br s, 1H), 2.50 (m, 6H), 1.54 (s, 3H), MS (EI) forC₁₄H₁₆N₆O: 285.0 (MH⁺).

Example 4

3-Chloroperbenzoic acid (0.565 g, 3.27 mmol) was added to a solution of6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-c]pyrimidin-7(8H)-one(0.308 g, 0.980 mmol) in dichloromethane (5.0 mL) at room temperature.After 30 minutes, the reaction was diluted with dichloromethane (50 mL)and washed twice with saturated NaHCO₃, followed by brine. The organicphase was separated and dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was precipitated with ethyl acetate to provide8-ethyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (302mg, 89% yield) as a yellow solid.

To a stirred solution of (76.5 mg, 0.221 mmol) in 1.5 mL of CH₂Cl₂ wasadded isopropyl amine (709.9 mg, 12.0 mmol, 54 eq.) The reaction wasstirred for 15 h at room temperature. The reaction was diluted withCH₂Cl₂ and extracted with 2N NaOH, H₂O, and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude material waspurified using preparative HPLC. Lyophillization of the productcontaining fractions afforded 19.9 mg (27.6% yield) of6-bromo-8-ethyl-2-(isopropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 5.30 (bs, 1H), 4.48 (bd, 2H),4.18 (bs, 1H), 2.52 (s, 3H), 1.62 (bs, 3H), 1.29 (m, 9H), MS (EI) forC₁₃H₁₇BrN₄O: 325.2 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 4b

6-bromo-2-(tert-butylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 5.47 (bs, 1H), 4.48 (m, 2H),2.50 (s, 3H), 1.58 (bs, 3H), 1.49 (s, 9H), MS (EI) for C₁₄H₁₉BrN₄O:339.2 (MH⁺)

Example 4c

6-Bromo-2-(cyclopentylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.07 (s, 1H), 5.89 (bs, 1H), 4.49 (bd, 2H),2.51 (s, 3H), 2.07 (m, 2H), 1.71 (m, 2H), 1.58 (m, 2H), 1.31 (t, 3H), MS(EI) for C₁₅H₁₉BrN₄O: 351.2 (MH⁺)

Example 4d

6-Bromo-2-(cyclohexylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.07 (s, 1H), 5.41 (bs, 1H), 4.47 (bd, 2H),3.84 (bs, 1H), 2.51 (s, 3H), 2.05 (d, J=12.4 Hz, 2H), 1.77 (m, 2H), 1.64(br m, 4H), 1.39 (m, 2H), 1.30 (m, 3H), MS (EI) for C₁₆H₂₁BrN₄O: 365.2(MH⁺)

Example 4e

6-Bromo-8-ethyl-4-methyl-2-(2-morpholinoethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 6.22 (bs, 1H), 4.48 (q, J=6.4Hz, 2H), 3.74 (t, J=4.4 Hz, 1H), 3.57 (q, J=4.8 Hz, 3H), 2.98 (bs, 2H),2.63 (t, J=6.0 Hz, 2H), 2.53 (s, 3H), 1.30 (t, J=6.8 Hz, 2H), MS (EI)for C₁₆H₂₂BrN₅O: 396.2 (MH⁺)

Example 4f

6-Bromo-8-ethyl-4-methyl-2-[(3-morpholino-4-ylpropyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.07 (s, 1H), 6.23 (bs, 1H), 4.47 (bs, 1H),3.75 (m, 4H), 3.57 (m, 2H), 2.52 (m, 4H), 2.48 (m, 2H), 1.82 (m, 2H),1.28 (s, 3H), MS (EI) for C₁₇H₂₄BrN₅O: 410.2 (MH⁺)

Example 4g

6-Bromo-2-{[3-(dimethylamino)propyl]amino}-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 7.26 (bs, 1H), 4.47 (m, 2H),3.54 (m, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.52 (s, 3H), 2.50 (s, 3H), 2.04(s, 3H), 2.00 (m, 2H), 1.29 (t, J=7.2 Hz, 3H), MS (EI) for C₁₅H₂₂BrN₅O:369.2 (MH⁺)

Example 4h

8-Ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: ¹H NMR(400 MHz, CDCl₃): δ 7.67 (d, J=9.2 Hz, 1H), 6.39 (d, J=9.2 Hz, 1H), 5.31(bs, 1H), 2.54 (s, 3H), 4.32 (q, J=6.8 Hz, 2H), 3.52 (q, J=6.8 Hz, 2H),2.53 (s, 3H), 1.15 (m, 6H); MS (EI) for C₁₂H₁₆N₄O: 233.2 (MH⁺).

Example 4j

6-Bromo-2-{[2-(dimethylamino)ethyl]amino}-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.37 (s, 1H), 7.83 (bt, J=8.0 Hz, 1H), 4.34(q, J=8.0 Hz, 2H), 3.42 (q, J=4.0 Hz, 2H), 2.51 (s, 3H), 2.45 (t, J=4.0Hz, 2H), 1.83 (s, 6H), 1.20 (t, J=8.0 Hz, 3H); MS (EI) for C₁₄H₂₀BrN₅O:354.3 (M⁺).

Example 4k

6-bromo-2-(ethylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1H), 6.66 (bs, 1H), 5.83 (sept,J=6.8 Hz, 1H), 3.54 (dq, J=12.8, 7.6 Hz, 2H), 2.62 (s, 3H), 1.60 (d,J=6.8 Hz, 6H), 1.34 (t, J=7.2 Hz, 3H); MS (EI) for C₁₃H₁₇BrN₄O: 324.9(M⁺).

Example 4m

6-Bromo-8-ethyl-4-methyl-2-morpholiN-4-ylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 4.45 (q, J=6.8 Hz, 2H), 3.92(s, 3H), 3.79 (s, 3H), 2.55 (s, 3H), 1.30 (t, J=6.8 Hz, 3H); MS (EI) forC₁₄H₁₇BrN₄O₂: 355.1 (M2H⁺).

Example 4n

6-Bromo-8-ethyl-4-methyl-2-[(phenylmethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.32 (m, 5H), 5.86 (bs, 1H),4.68 (s, 2H), 4.43 (q, J=7.2 Hz, 2H), 2.54 (s, 3H), 1.13 (t, J=7.2 Hz,3H); MS (EI) for C₁₇H₁₇BrN₄O: 375.1 (M2H⁺).

Example 4p

6-Bromo-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 5.71 (bs, 1H), 4.48 (bs, 2H),3.54 (q, J=6.8 Hz, 2H), 2.53 (s, 3H), 1.16 (m, 6H); MS (EI) forC₁₂H₁₅BrN₄O: 311.9 (MH⁺).

Example 52-(Ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Pd(dppf) dichloromethane adduct (0.077 g, 0.095 mmol) was added to asuspension of6-bromo-2-(ethylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.154 g, 0.474 mmol), 2-thiophene boronic acid (0.079 g, 0.616 mmol),and triethylamine (165 μL, 1.19 mmol) in 10:1 DME:water (1.5 mL). Thereaction was heated to 100° C. After 5 h, the reaction was cooled toroom temperature, filtered though a Celite plug and concentrated invacuo. The residue was purified on SiO₂ (3:2 hexanes:ethyl acetate) togive2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one(28 mg, 18% yield) as a light yellow solid: ¹H NMR (400 MHz, CDCl₃): δ8.06 (s, 1H), 7.60 (dd, J=4.0, 1.2 Hz, 1H), 7.38 (dd, J=5.2 , 0.8 Hz,1H), 7.10 (dd, J=4.8, 3.2 Hz, 1H), 5.93 (bsept, 1H), 5.13 (bs, 1H), 3.54(pent, J=7.2 Hz, 2H), 2.61 (s, 3H), 1.66 (d, J=6.8 Hz, 6H), 1.28 (t,J=7.6 Hz, 3H); MS (EI) for C₁₇H₂₀N₄OS: 329.0 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 5a

2-(Ethylamino)-6-furan-2-yl-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHZ, CDCL₃): δ 8.43 (S, 1H), 7.81 (S, 1H), 7.47 (T, J=2 HZ,1H), 6.75 (DD, J=2.0 , 0.8 HZ, 1H), 5.92 (BSEPT, 1H), 5.25 (BS, 1H),3.53 (DQ, J=12.5, 7.6 HZ, 2H), 2.60 (S, 3H), 1.65 (D, J=6.8 HZ, 6H),1.29 (T, J=7.2 HZ, 3H); MS (EI) FOR C₁₇H₂₀N₄O₂: 313.1 (MH⁺).

Example 5b

2-(Ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 7.61 (d, J=2.0 Hz, 1H), 6.65(bs, 1H), 5.93 (bs, 1H), 5.44 (bs, 1H), 3.55 (dq, J=12.8, 6.4 Hz, 2H),2.62 (s, 3H), 1.66 (d, J=6.4 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H); MS (EI)for C₁₆H₂₀N₆O: 313.3 (MH⁺).

Example 5c

2-(Ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, MeOH-d₄:TFA-d, 10:1): δ 8.59 (s, 1H), 8.07 (s, 1H),7.30 (s, 1H), 3.59 (q, J=8.0 Hz, 2H), 2.88 (s, 3H), 1.28 (t, J=8.0 Hz,3H); MS (EI) for C₁₃H₁₄N₆O: 271.0 (MH⁺).

Example 5e

8-Cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.32 (s, 1H), 7.80 (s, 1H), 7.59 (s, 1H),6.916 (s, 1H), 5.95 (m, 1H), 2.35 (bs, 2H), 1.95 (bs, 2H), 1.73 (bs,2H), 1.61 (bs, 2H), 1.12 (t, J=6.8 Hz, 3H), MS (EI) for C_(18H22)N₆O:339.1 (MH⁺)

Example 5f

6-(2,4-Difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, 2H), 7.52 (m, 1H), 6.85 (m, 2H),5.38 (bs, 1H), 4.48 (m, 2H), 3.56 (m, 2H), 2.57 (s, 3H), 1.39 (m, 6H);MS (EI) for C_(18H18)F₂N₄O: 345.1 (MH⁺).

Example 5g

6-(3-Chloro-4-fluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.79 (s, 2H), 7.57 (m, 1H), 7.19 (m, 1H),5.41 (bs, 1H), 4.45 (bs, 2H), 3.58 (m, 2H), 2.59 (m, 3H), 1.36 (m, 6H);MS (EI) for C_(18H18)ClFN₄O: 361.0 (MH⁺).

Example 5h

6-(2,4-Dichlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, 1H), 7.42 (d, 1H), 7.38 (m, 2H),5.38 (bs, 1H), 4.42 (m, 2H), 3.59 (m, 2H), 2.56 (s, 3H), 1.24 (m, 6H);MS (EI) for C_(18H18)Cl₂N₄O: 377.0 (M⁺), 379.0 (M+2)

Example 5i

6-(3,4-Difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.79 (s, 1H), 7.59 (m, 1H), 7.39 (m, 1H),7.18 (m, 1H), 5.39 (bs, 1H), 4.46 (m, 2H), 3.58 (m, 2H), 2.59 (s, 3H),1.27 (m, 6H); MS (EI) for C_(18H18)F₂N₄O: 345.1 (MH⁺).

Example 5j

8-Ethyl-2-(ethylamino)-4-methyl-6-[4-(phenyloxy)phenyl]pyrido[2,3-c]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.78 (s, 1H), 7.63 (d, 2H), 7.39 (t, 2H),7.16 (t, 1H), 7.04 (d, 4H), 5.38 (bs, 1H), 4.47 (m, 2H), 3.57 (m, 2H),2.59 (s, 3H), 1.26 (m, 6H); MS (EI) for C₂₄H₂₄N₄O₂: 401.1 (MH⁺).

Example 5k

8-Ethyl-2-(ethylamino)-4-methyl-6-naphthaleN-1-ylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.84 (d, 2H), 7.80 (s, 1H), 7.73 (d, 1H),7.48 (m, 4H), 539 (bs, 1H), 4.55 (bs, 2H), 3.59 (m, 2H), 2.54 (s, 3H),1.37 (m, 6H); MS (EI) for C₂₂H₂₂N₄O: 359.1 (MH⁺).

Example 5m

8-Ethyl-2-(ethylamino)-4-methyl-6-[3-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.82 (m, 3H), 7.56 (m, 2H), 5.59 (bs, 1H),4.47 (d, 2H), 3.51 (m, 2H), 2.58 (s, 3H), 1.30 (m, 6H); MS (EI) forC₁₉H₁₉F₃N₄O: 377.1 (MH⁺).

Example 5n

8-Ethyl-2-(ethylamino)-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.64 (dd, J=3.60, 1.20 Hz, 1H),7.38 (dd, J=5.20, 1.20 Hz, 1H), 7.10 (dd, J=4.78, 3.60 Hz, 2H), 3.54(qn, 2H), 2.62 (s, 3H), 1.30 (m, 6H); MS (EI) for C₁₆H₁₈N₄OS: 315.0(MH⁺).

Example 5p

6-(3-Chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.78 (s, 1H), 7.65 (s, 1H), 7.56 (dd, 1H),7.34 (m, 2H), 5.39 (bs, 1H), 4.43 (m, 2H0, 3.57 (m, 2H), 2.59 (s, 3H),1.32 (m, 6H); MS (EI) for C_(18H19)ClN₄O: 343.0 (MH⁺).

Example 5q

6-(4-Chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.77 (s, 1H), 7.62 (dd, 2H0, 7.40 (dd, 2H),5.38 (bs, 1H), 4.47 (m, 2H), 3.58 (m, 2H), 2.59 (s, 3H), 1.39 (m, 6H);MS (EI) for C_(18H19)ClN₄O: 343.0 (MH⁺).

Example 5r

8-Ethyl-2-(ethylamino)-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.80 (m, 3H), 7.63 (dd, 2H), 5.39 (bs, 1H),4.51 (m, 2H), 3.58 (m, 2H), 2.58 (s, 3H), 1.33 (m, 6H); MS (EI) forC₁₉H₁₉F₃N₄O: 343.0 (MH⁺).

Example 5s

8-Ethyl-2-(ethylamino)-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.11 (dd, J=2.10, 0.90 Hz, 1H), 7.94 (s, 1H),7.52 (dd, J=3.90, 1.20 Hz, 1H), 7.35 (qr, 1H), 5.33 (bs, 1H), 4.52 (qr,2H), 3.54 (m, 2H), 2.58 (s, 3H), 1.28 (m, 6H); MS (EI) for C₁₆H₁₈N₄OS:315.0 (MH⁺).

Example 5t

8-Ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.01 (s, 1H), 7.52 (s, 1H), 6.93 (s, 1H),5.38 (bs, 1H), 4.58 (qr, 2H), 3.57 (m, 2H), 2.61 (s, 1H), 2.33 (s, 1H),1.60 (s, 3H); MS (EI) for C₁₇H₂₀N₄OS: 329.0 (MH⁺).

Example 5u

8-Ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.69 (s, 1H), 7.38 (d, 1H), 6.99 (m, 1H),5.35 (bs, 1H), 4.51 (qr, 2H), 3.57 (m, 2H), 2.58 (s, 3H), 2.22 (s, 3H),1.32 (m, 6H); MS (EI) for C₁₇H₂₀N₄OS: 329.0 (MH⁺).

Example 5v

1,1-Dimethylethyl2-[8-ethyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl]-1H-pyrrole-1-carboxylate:¹H NMR (400 MHz, CDCl₃): δ 7.65 (s, 1H), 7.38 (d, 1H), 6.22 (m, 2H),5.29 (bs, 1H), 4.41 (m, 2H), 3.57 (m, 2H), 2.56 (s, 3H), 1.41 (s, 9H),1.22 (m, 6H); MS (EI) for C₂₁H₂₇N₅O₃: 398.0 (MH⁺).

Example 5w

8-Ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 11.1 (bs, 1H), 7.99 (s, 1H), 6.85 (d, 1H),6.62 (d, 1H), 6.29 (d, 1H), 5.28 (bs, 1H), 4.57 (m, 2H), 3.56 (m, 2H),2.61 (s, 3H), 1.35 (m, 6H); MS (EI) for C₁₆H₁₉N₅O: 298.1 (MH⁺).

Example 5x

8-Ethyl-2-(ethylamino)-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.42 (s, 1H), 7.83 (s, 1H), 7.43 (s, 1H),6.76 (s, 1H), 5.37 (bs, 1H), 4.52 (m, 2H), 3.58 (m, 2H), 2.61 (s, 3H),1.30 (m, 6H); MS (EI) for C₁₆H₁₈N₄O₂: 299.1 (MH⁺).

Example 5y

8-Ethyl-2-(ethylamino)-4-methyl-6-[1-(phenylmethyl)-1H-pyrazol-4-yl]pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.39 (s, 1H), 7.98 (d, 1H), 7.96 (d, 1H),7.35 (m, 5H), 5.39 (s, 2H), 5.35 (bs, 1H), 4.52 (m, 2H), 3.58 (m, 2H),2.62 (s, 3H), 1.35 (m, 6H); MS (EI) for C₂₂H₂₄N₆O: 389.3 (MH⁺).

Example 5z

6-(3,5-Dimethylisoxazol-4-yl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.59 (s, 1H), 7.24 (s, 1H), 5.43 (bs, 1H),4.47 (bs, 2H), 3.56 (m, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 2.25 (s, 3H),1.29 (m, 6H); MS (EI) for C₁₇H₂₁N₅O₂: 328.1 (MH⁺).

Example 5aa

8-Ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 1H), 7.62 (s, 1H), 6.65 (d, 1H),5.43 (bs, 1H), 4.58 (m, 2H), 3.59 (m, 2H), 2.62 (s, 3H), 1.38 (m, 6H);MS (EI) for C₁₅H₁₈N₆O: 299.1 (MH⁺).

Example 5bb

8-Ethyl-4-methyl-6-(1H-pyrazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.18 (s, 1H), 7.63 (d, 1H), 6.73 (d, 1H),5.62 (bs, 1H), 4.58 (m, 2H), 4.30 (m, 2H), 2.74 (s, 3H), 1.35 (t, 3H);MS (EI) for C₁₅H₁₅F₃N₆O: 353.0 (MH⁺).

Example 5cc

8-Ethyl-2-(ethylamino)-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.87 (s, 1H), 7.98 (s, 1H), 7.43 (s, 1H),7.22 (s, 1H), 5.56 (bs, 1H), 4.58 (bs, 2H), 2.72 (s, 3H0, 1.36 (m, 6H);MS (EI) for C₁₅H₁₇N₅OS: 316.0 (MH⁺).

Example 66-Biphenyl-4-yl-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyridimidiN-7(8H)-one

2-Ethylamino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(60 mg, 0.194 mmol), K₂CO₃ (81.0 mg, 3.0 equiv.), biphenyl boronic acid(17.8 mg, 1.5 equiv.) and Pd(PPh₃)₄ (10 mol %, 225 mg) were added todioxane/H₂O (10 mL/3 mL). The reaction was heated to 95° C. and stirredfor 2 h. The reaction mixture was partitioned between organic andaqueous layers with ethyl acetate (20 mL) and H₂O (10 mL) and saturatedaqueous NaCl (5 mL). The organic layer was dried over anhydrousmagnesium sulfate, filtered and evaporated to give6-Biphenyl-4-yl-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyridimidiN-7(8H)-one(48.42 mg, 65% yield): ¹H NMR (400 MHz, CDCl₃): δ 7.81 (s, 1H), 7.74 (m,2H), 7.60 (m, 4H), 7.42 (m, 2H), 7.38 (m, 1H), 4.50 (q, 2H), 3.60 (q,2H), 2.60 (s, 3H), 1.30 (m, 6H); MS (EI) for C₂₄H₂₄N₄O: 385.1 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 6a

8-Ethyl-2-(ethylamino)-4-methyl-6-[4-(methyloxy)phenyl]pyrido[2,3-d]pyridimidiN-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.81 (s, 1H), 7.60 (d, 2H), 6.96 (d, 2H),4.50 (q, 2H), 3.82 (s, 3H), 3.58 (q, 2H), 2.58 (s, 3H), 1.30 (m, 6H); MS(EI) for C₁₉H₂₂N₄O₂: 339.1 (MH⁺).

Example 6b

8-Ethyl-2-(ethylamino)-4-methyl-6-[2-(methyloxy)phenyl]pyrido[2,3-d]pyridimidiN-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.81 (s, 1H), 7.60 (d, 2H), 6.96 (d, 2H),4.50 (q, 2H), 3.80 (s, 3H), 3.58 (q, 2H), 2.50 (s, 3H), 1.30 (m, 6H); MS(EI) for C₁₉H₂₂N₄O₂: 339.1 (MH⁺).

Example 6c

6-[2,4-Bis(methyloxy)phenyl]-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.70 (s, 1H), 7.30 (s, 1H), 6.60 (m, 2H),4.50 (q, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.45 (q, 2H), 2.50 (s, 3H),1.30 (m, 6H); MS (EI) for C₂₀H₂₄N₄O₃: 369.1 (MH⁺).

Example 6d

8-Ethyl-2-(ethylamino)-4-methyl-643-(methyloxy)phenyl)pyrido[2,3-d]pyridimidiN-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.81 (s, 1H), 7.60 (d, 2H), 6.96 (d, 2H),4.50 (q, 2H), 3.80 (s, 3H), 3.58 (q, 2H), 2.50 (s, 3H), 1.30 (m, 6H); MS(EI) for C₁₉H₂₂N₄O₂: 339.1 (MH⁺).

Example 6e

8-(5-Chloro-2-thienyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.00 (s, 1H), 7.38 (d, 2H), 6.96 (d, 2H),4.50 (q, 2H), 3.58 (q, 2H), 2.60 (s, 3H), 1.30 (m, 6H); MS (EI) forC₁₆H₁₇ClN₄OS: 349.2 (MH⁺).

Example 6f

8-Ethyl-2-(ethylamino)-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyridimidiN-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.19 (s, 1H), 9.16 (s, 1H), 8.23 (s, 1H),8.00 (m, 1H), 4.38 (q, 2H), 3.40 (q, 2H), 2.50 (s, 3H), 1.30 (m, 6H); MS(EI) for C₁₆H₁₈N₆O: 311.3 (MH⁺).

Example 6g

8-Ethyl-2-(ethylamino)-6-(3-fluoropyridiN-4-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.58 (s, 1H), 8.42 (d, 1H), 7.98 (s, 1H),7.60 (t, 1H), 4.50 (q, 2H), 3.58 (q, 2H), 2.60 (s, 3H), 1.30 (m, 6H); MS(EI) for C₁₇H₁₈FN₅O: 328.3 (MH⁺).

Example 6h

8-Ethyl-2-(ethylamino)-6-(1H-indole-6-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 11.2 (s, 1H), 7.90 (s, 1H), 7.88 (s, 1H),7.42 (s, 2H), 7.38 (s, 1H), 6.50 (s, 1H), 4.40 (q, 2H), 3.40 (q, 2H),2.42 (s, 3H), 1.30 (m, 6H); MS (EI) for C₂₀H₂₁N₅O: 348.3 (MH⁺).

Example 6i

8-Ethyl-2-(ethylamino)-4-methyl-6-(5-phenyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (s, 1H), 7.81 (d, 1H), 7.70 (d, 2H),7.50 (d, 1H), 7.42 (m, 2H), 7.30 (m, 1H), 4.40 (q, 2H), 3.40 (q, 2H),2.42 (s, 3H), 1.30 (m, 6H); MS (EI) for C₂₂H₂₂N₄OS: 391.3 (MH⁺).

Example 6j

8-Ethyl-2-(ethylamino)-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.78 (s, 1H), 7.46 (m, 5H), 5.41 (bs, 1H),4.50 (q, J=6.8 Hz, 2H), 3.60 (m, 2H), 2.57 (s, 3H), 1.30 (m, 6H); MS(EI) for C_(18H20)N₄O: 309.2 (MH⁺).

Example 6k

8-Ethyl-2-(ethylamino)-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.79 (s, 1H), 7.46-7.02 (m, 4H), 5.41 (bs,1H), 4.51 (q, J=6.4 Hz, 2H), 3.55 (q, J=6.8 Hz, 2H), 2.58 (s, 3H), 1.34(t, J=6.80 Hz, 3H), 1.29 (t, J=6.40 Hz, 3H); MS (EI) for C_(18H19)FN₄O:327.3 (MH⁺).

Example 6m

8-ethyl-2-(ethylamino)-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.80 (s, 1H), 7.52-7.12 (m, 4H), 5.33 (bs,1H), 4.49 (q, J=6.8 Hz, 2H), 3.53 (q, J=7.2 Hz, 2H), 2.55 (s, 3H), 1.34(t, J=7.20 Hz, 3H), 1.28 (t, J=6.80 Hz, 3H); MS (EI) for C_(18H19)FN₄O:327.3 (MH⁺).

Example 6n

8-ethyl-2-(ethylamino)-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, 1H), 7.66-7.08 (m, 4H), 5.30 (bs,1H), 4.52 (q, J=6.4 Hz, 2H), 3.54 (q, J=6.8 Hz, 2H), 2.58 (s, 3H), 1.34(t, J=6.80 Hz, 3H), 1.29 (t, J=6.40 Hz, 3H); MS (EI) for C_(18H19)FN₄O:327.3 (MH⁺).

3-Chloroperbenzoic acid (1.78 g, 10.4 mmol) was added to a solution of6-bromo-4-methyl-8-(1-methylethyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(1.33 g, 4.14 mmol), prepared using procedures similar to thosedescribed in Example 1, in dichloromethane (30.0 mL) at roomtemperature. After 1, the reaction was diluted with dichloromethane (50mL) and washed twice with saturated NaHCO₃, followed by brine. Theorganic phase was separated and dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was precipitated with ethylacetate/hexanes to provide the corresponding sulfone (1.31 g, 93% yield)as an off-white solid.

Example 82-Amino-4-methyl-8-(phenylmethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

Triethylamine (3.4 mL, 24.6 mmol) was added to a suspension of2-amino-4-chloro-6-methylpyrimidine (Aldrich, 1.77 g, 12.3 mmol) andbenzylamine (1.98 g, 18.5 mmol) in anhydrous dioxane (20 mL). Thereaction was heated to 80° C. and allowed to run for 12 h. Upon coolingto room temperature, a white precipitate formed which was collected byvacuum filtration. The solid was recrystallized from acetone: hexanes toafford N⁴-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 89% yield) as awhite solid.

Iodine (3.04 g, 12.0 mmol) was added to a solution ofN⁴-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 10.9 mmol) inanhydrous MeOH (50 mL) at 0° C. The reaction was allowed to warm to roomtemperature overnight. After 12 hours, an additional 0.5 equiv of iodinewas added, and the reaction warmed to 50° C. After four hours, thereaction was cooled to room temperature and concentrated in vacuo. Theresidue was diluted with ethyl acetate (200 mL) and washed with 10%NaHSO₃ (200 mL). The aqueous phase was separated and washed once morewith ethyl acetate (200 mL). The organic phases were combined, washedwith brine, separated and dried over Na₂SO₄, The filtrate wasconcentrated in vacuo to afford the productN⁴-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 85% yield).

Triethylamine (7.60 mL, 54.5 mmol) was added to a suspension ofN⁴-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 10.9 mmol),ethyl acrylate (3.55 mL, 32.7 mmol) and Pd(PPh₃)₄ (629 mg, 0.545 mmol)in anhydrous DMF (20 mL). The reaction was heated to 95° C. undernitrogen. After 24 h, the reaction was allowed to cool to roomtemperature and concentrated in vacuo. The residue was poured into a 10%solution of LiCl and washed with ethyl acetate (100 mL). The organicphase was separated and washed with brine, separated and dried overNa₂SO₄. The filtrate was concentrated in vacuo and purified on SiO₂ (3:2methylene chloride:ethyl acetate) to afford(E)-ethyl-3-(2-amino-4-(benzylamino)-6-methylpyrimidin-5-yl)acrylate(0.954 g, 28% yield) as a light yellow solid.

2-amino-4-methyl-8-(phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-oneDiazabicyclo[5.4.0]undec-7-ene (DBU) (1.83 mL, 12.2 mmol) was added to aflask charged with(E)-ethyl-3-(2-amino-4-(benzylamino)-6-methylpyrimidin-5-yl)acrylate(0.954 g, 3.05 mmol) and the reaction refluxed at 160° C. under anitrogen atmosphere. After 20 hours, the reaction was cooled to roomtemperature and concentrated in vacuo. Purification on SiO₂ (1:1methylene chloride:ethyl acetate) afforded the product (0.508 g, 62%yield) as an off-white solid.

Bromine (72 μL, 1.40 mmol) was added to a suspension of2-amino-4-methyl-8-(phenylmethyl)pyrido[2,3-c]pyrimidin-7(8H)-one (0.340g, 1.27 mmol) in methylene chloride (20 mL) at 0° C. The reaction wasallowed to warm to room temperature over one hour and the resultingprecipitate collected by vacuum filtration to afford2-amino-6-bromo-4-methyl-(8-phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.435 g, 99% yield) after drying. The yellow solid was used in the nextstep without further purification.

A 10:1 solution of dioxane and water (11 mL) was added to a flaskcharged with2-amino-6-bromo-4-methyl-(8-phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.435 g, 1.27 mmol), 1H-pyrazole-5-boronic acid (0.284 g, 2.54 mmol),Pd(PPh₃)₄ (0.073 mg, 0.063 mmol), and K₂CO₃ (0.527 g, 3.81 mmol). Theflask was flushed with nitrogen and fitted with a reflux condenser andheated to 110° C. After 12 h the reaction was cooled to room temperatureand diluted with ethyl acetate (100 mL) and washed with water. Theaqueous phase was acidified to pH 1.0 and washed with ethyl acetate (100mL). The organic phases were combined and washed with brine, separatedand dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas precipitated with ethyl acetate to give2-Amino-4-methyl-8-(phenylmethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.062 g, 15% yield) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆): δ13.10 (bs, 1H), 12.93 (bs, 1H), 8.47 (s, 1H), 7.76 (bs, 1H), 7.51 (bs,1H), 7.28 (m, 5H), 6.97 (s, 1H), 5.55 (s, 2H), 2.55 (bs, 3H); MS (EI)for C₁₈H₁₆N₆O: 333.1 (MH⁺).

Example 92-Amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one

A 3:1 solution of dioxane and water (4 mL) was added to a flask chargedwith 2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(0.140 g, 0.495 mmol) from above, 4-methylthiophene-3-boronic acid(0.140 g, 0.989 mmol), Pd(PPh₃)₄ (0.057 mg, 0.050 mmol), and K₂CO₃(0.205 g, 1.48 mmol). The flask was flushed with nitrogen and fittedwith a reflux condenser and heated to 100° C. After 12 hours thereaction was cooled to room temperature and diluted with ethyl acetate(70 mL) and washed with water. The aqueous phase was separated andwashed with an additional amount of ethyl acetate (70 mL). The organicphases were combined and washed with brine, separated and dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified onSiO₂ (1:1 methylene chloride:ethyl acetate) to give2-Amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.081 g, 55% yield) as an off-white solid: ¹H NMR (400 MHz, DMSO-d₆): δ7.84 (s, 1H), 7.46 (d, J=4.0 Hz, 1H), 7.19 (m, 3H), 4.32 (q, J=8.0 Hz,2H), 2.52 (s, 3H), 2.11 (bs, 3H), 1.19 (t, J=8.0 Hz, 3H); MS (EI) forC₁₅H₁₆N₄OS: 301.1 (MH⁺).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 9a

2-Amino-8-ethyl-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.11 (dd, J=2.8, 1.2 Hz, 1H), 7.95 (s, 1H),7.51 (dd, J=5.2, 1.2 Hz, 1H), 7.37 (dd, J=4.8, 3.2 Hz, 1H), 5.21, (bs,2H), 4.48 (q, J=6.8 Hz, 2H), 2.63 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); MS(EI) for C₁₄H₁₄N₄OS: 287.0 (MH⁺).

Example 9b

2-Amino-8-ethyl-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.47 (bs, 1H), 7.85 (s, 1H), 7.49 (t, J=1.6Hz, 1H), 6.77 (dd, J=2.0, 0.8 Hz, 1H), 5.19, (bs, 2H), 4.48 (q, J=6.8Hz, 2H), 2.64 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); MS (EI) for C₁₄H₁₄N₄O₂:271.1 (MH⁺).

Example 9c

2-Amino-6-(3,5-dimethylisoxazol-4-yl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.62 (s, 1H), 5.27, (bs, 2H), 4.44 (q, J=7.2Hz, 2H), 2.59 (s, 3H), 2.38 (s, 3H), 2.25 (s, 3H), 1.31 (t, J=6.8 Hz,3H); MS (EI) for C₁₅H₁₇N₅O₂: 300.1 (MH⁺).

Example 9d

2-Amino-8-ethyl-6-isoxazol-4-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 9.36 (s, 1H), 8.71 (s, 1H), 7.91 (s, 1H),5.30, (bs, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 1.32 (t, J=6.8 Hz,3H); MS (EI) for C₁₃H₁₃N₅O₂: 272.0 (MH⁺).

Example 9e

2-Amino-8-ethyl-6-furan-2-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.48 (d, J=0.8 Hz, 1H), 7.37(d, J=3.6 Hz, 1H), 6.53 (dd, J=3.6, 2.0 Hz 1H), 5.21, (bs, 2H), 4.48 (q,J=7.2 Hz, 2H), 2.66 (s, 3H), 1.32 (t, J=6.8 Hz, 3H); MS (EI) forC₁₄H₁₄N₄O₂: 271.0 (MH⁺).

Example 9f

5-(2-Amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)thiophene-2-carbonitrile:¹H NMR (400 MHz, CDCl₃): δ 8.24 (s, 1H), 7.61 (d, J=4.4 Hz, 1H), 7.55(d, J=4.4 Hz, 1H), 5.33, (bs, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.68 (s, 3H),1.33 (t, J=6.8 Hz, 3H); MS (EI) for C₁₅H₁₃N₅OS: 312.0 (MH⁺).

Example 9g

2-Amino-8-ethyl-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 12.88 (s, 1H), 8.38 (s, 1H), 8.17 (s, 2H),7.10 (bs, 2H), 4.35 (q, J=7.2 Hz, 2H), 2.59 (s, 3H), 1.20 (t, J=7.2 Hz,3H); MS (EI) for C₁₃H₁₄N₆O: 271.0 (MH⁺).

Example 9h

2-Amino-8-ethyl-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 8.94 (s, 1H), 7.94 (d, J=3.2 Hz, 1H), 7.46(d, J=3.2 Hz, 1H), 5.34 (bs, 2H), 4.54 (q, J=7.2 Hz, 2H), 2.73 (s, 3H),1.35 (t, J=7.2 Hz, 3H); MS (EI) for C₁₃H₁₃N₅OS: 288.0 (MH⁺).

Example 9i

2-Amino-8-ethyl-4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (s, 1H), 7.20 (bs, 2H), 6.81 6.11 (dd,J=3.6, 2.0 Hz, 1H), 6.02 (t, J=3.2 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.49(s, 3H), 2.52 (s, 3H), 1.19 (t, J=7.2 Hz, 3H); MS (EI) for C₁₅H₁₇N₅O:284.1 (MH⁺).

Example 9j

2-Amino-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one: ¹HNMR (400 MHz, CDCl₃): δ 7.79 (s, 1H), 7.65 (d, J=6.8 Hz, 2H), 7.43 (d,J=7.2 Hz, 2H), 7.36 (d, J=7.2 Hz, 1H), 5.24 (bs, 2H), 4.47 (q, J=7.2 Hz,2H), 2.60 (s, 3H), 1.31 (d, J=7.2 Hz, 3H), MS (EI) for C₁₆H₁₆N₄O: 281.2(MH⁺)

Example 9k

2-Amino-8-ethyl-6-(4-methoxyphenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 6.96(d, J=8.8 Hz, 2H), 5.17 (bs, 2H), 4.47 (q, J=6.8 Hz, 2H), 3.85 (s, 3H),2.60 (s, 3H), 1.31 (d, J=7.2 Hz, 3H), MS (EI) for C₁₇H₁₈N₄O₂: 311.2(MH⁺)

Example 9m

2-Amino-8-ethyl-6-(2-methoxyphenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.75 (m, 1H), 7.36 (m, 2H), 7.01 (m, 2H),5.20 (bs, 2H), 4.45 (m, 2H), 3.82 (s, 3H), 2.56 (s, 3H), 1.31 (m, 3H),MS (EI) for C₁₇H₁₈N₄O₂: 311.2 (MH⁺)

Example 9n

2-Amino-6-(4-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.78 (s, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.39(d, J=8.8 Hz, 2H), 5.23 (bs, 2H), 4.46 (q, J=7.2 Hz, 2H), 2.61 (s, 3H),1.31 (d, J=6.8 Hz, 3H), MS (EI) for C₁₆H₁₅ClN₄O: 315.1 (MH⁺)

Example 9p

2-Amino-6-(3-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.79 (s, 1H), 7.66 (m, 1H), 7.56 (m, 1H),7.35 (m, 2H), 5.25 (bs, 2H), 4.46 (q, J=5.6 Hz, 2H), 2.61 (s, 3H), 1.31(d, J=7.2 Hz, 3H), MS (EI) for C₁₆H₁₅ClN₄O: 315.1 (MH⁺)

Example 9q

2-Amino-6-(2-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, 1H), 7.67 (m, 1H), 7.54 (m, 2H),7.38 (m, 1H), 7.333 (m, 1H), 5.22 (bs, 2H), 4.46 (q, J=6.8 Hz, 2H), 2.57(s, 3H), 1.31 (d, J=6.8 Hz, 3H), MS (EI) for C₁₆H₁₅ClN₄O: 315.1 (MH⁺)

Example 9r

2-Amino-6-(2,4-dichlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃): δ 7.77 (s, 1H), 7.67 (m, 1H), 7.49 (m, 1H),7.32 (m, 1H), 5.24 (bs, 2H), 4.45 (q, J=6.8 Hz, 2H), 2.58 (s, 3H), 1.30(d, J=7.2 Hz, 3H), MS (EI) for C₁₆H₁₄Cl₂N₄O: 349.1 (MH⁺)

Example 9t

2-Amino-8-ethyl-4-methyl-6-(2-thienyl)pyrido[2,3-a]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (s, 1H), 7.85-7.13 (m, 5H), 4.37 (q,J=7.2 Hz, 2H), 2.62 (s, 3H), 1.18 (t, J=7.2 Hz, 3H); MS (EI) forC₁₄H₁₄N₄OS: 287.1 (MH⁺).

Example 9u

2-Amino-8-ethyl-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 7.99 (s, 1H), 7.76-7.22 (m, 6H), 4.34 (q,J=7.2 Hz, 2H), 2.56 (s, 3H), 1.20 (t, J=7.2 Hz, 3H); MS (EI) forC₁₆H₁₅FN₄O: 299.2 (MH⁺).

Example 9v

2-Amino-8-ethyl-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.06 (s, 1H), 7.61-7.44 (m, 3H), 7.29 (bs,2H), 7.20-7.15 (m, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.58 (s, 3H), 1.20 (t,J=7.2 Hz, 3H); MS (EI) for C₁₆H₁₅FN₄O: 299.2 (MH⁺).

Example 9w

2-Amino-8-ethyl-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (s, 1H), 7.50-7.23 (m, 6H), 4.32 (q,J=6.8 Hz, 2H), 2.52 (s, 3H), 1.19 (t, J=6.8 Hz, 3H); MS (EI) forC₁₆H₁₅FN₄O: 299.2 (MH⁺).

Example 9x

Methyl3-(2-amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)benzoate:¹H NMR (400 MHz, DMSO-d₆): δ 8.34 (s, 1H), 8.06 (s, 1H), 7.95-7.55 (m,3H), 7.28 (bs, 1H), 4.35 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 2.58 (s, 3H),1.21 (t, J=6.8 Hz, 3H); MS (EI) for C_(18H18)N₄O₃: 339.2 (MH⁺).

Example 9y

2-Amino-8-ethyl-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (s, 1H), 7.65-7.30 (m, 5H), 4.31 (q,J=7.2 Hz, 2H), 2.50 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); MS (EI) forC₁₄H₁₄N₆O: 283.2 (MH⁺).

Example 102-Amino-8-ethyl-6-(1H-imidazol-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

A solution of potassium hydroxide (0.139 g, 2.48 mmol) in absoluteethanol (3.0 mL) was added to a pressure tube charged with4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (0.229g, 1.08 mmol), prepared using procedures similar to those described forIntermediate 1, and 2-(1H-imidazol-5-yl)acetonitrile (0.174 g, 162 mmol)and heated to 70° C. After 12 h, the reaction was allowed to cool toroom temperature and concentrated in vacuo affording8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-imineas a solid. The product was used in the subsequent step without furtherpurification.

Acetic anhydride (15.0 mL) was added to a flask charged with crude8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-c]pyrimidin-7(8H)-imineand heated to 100° C. After 30 minutes, the reaction was allowed to coolto room temperature and concentrated in vacuo. The acetylated residuewas then treated with 6 N HCl (16 mL) and heated to 95° C. for 30minutes then transferred to a large flask. A saturated solution ofNaHCO₃ (150 mL) was added at 0° C. to about pH=8.0. The aqueous phasewas washed thrice with ethyl acetate (100 mL) and the organic layerscombined, then washed with brine and dried over Na₂SO₄. The drying agentwas filtered off and the organic layers were concentrated in vacuo toafford crude8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-onewhich was used in the subsequent step without further purification.

3-Chloroperbenzoic acid (0.299 g, 1.73 mmol) was added to a solution ofcrude8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(0.260 g, 0.866 mmol) in dichloromethane (10.0 mL) at room temperature.After 1.5 h, the reaction was diluted with dichloromethane (50 mL) andwashed twice with saturated NaHCO₃, followed by brine. The organic phasewas separated and dried over Na₂SO₄, filtered, and concentrated invacuo. The corresponding sulfone was used in the subsequent step withoutfurther purification.

Concentrated aqueous ammonium hydroxide (400 μL) was added to a solutionof the sulfone in dioxane (10 mL) at 0° C. The reaction flask sealed,and allowed to warm to room temperature upon standing overnight. Thereaction was concentrated in vacuo and purified on reverse phase HPLC(acetonitrile: water 0.1% TFA, 20-60% gradient). The fractionscontaining product were collected and concentrated to one half volumeand poured into saturated NaHCO₃ (50 mL). The aqueous phase was washedtrice with ethyl acetate (50 mL) and dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was triturated with methylenechloride and ethyl acetate to afford2-amino-8-ethyl-6-(1H-imidazol-5-yl)-4-methylpyrido[2,3-c]pyrimidin-7(8H)-one(29 mg, 12% yield) as a light yellow solid: ¹H NMR (400 MHz, CH₃OH-d₄):δ 8.52 (bs, 1H), 7.88 (bs, 1H), 7.76 (s, 1H), 4.30 (q, J=6.8 Hz, 2H),2.65 (s, 3H), 1.29 (t, J=6.8 Hz, 3H); MS (EI) for C₁₃H₁₄N₆O: 271.0(MH⁺).

Example 112-Amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-c]pyrimidin-7(8H)-one

Trimethylsilylethyne (1.44 mL, 10.2 mmol) was added to a pressure tubecharged with2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.58g, 5.59 mmol) from above, CuI (0.053 g, 0.279 mmol), and PdCl₂(PPh₃)₂(0.211 g, 0.279 mmol) in triethylamine (20 mL). The pressure tube wassealed under nitrogen and heated to 50° C. 96 h. The reaction was cooledto room temperature and poured into a saturated solution of NaHCO₃ (150mL), then washed four times with ethyl acetate (50 mL). The organiclayers were pooled and dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified on SiO₂ (2:1, methylene chloride:ethylacetate) to afford2-amino-8-ethyl-4-methyl-6-((trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one(1.09 g, 65% yield) as an off white solid.

Potassium carbonate (1.00 g, 7.28 mmol) was added to a flask chargedwith2-amino-8-ethyl-4-methyl-6-((trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one(1.09 g, 3.64 mmol) in anhydrous methanol (15 mL). The reaction wasstirred at room temperature under nitrogen for 16 h. The reaction wasconcentrated to one half volume and the yellow precipitate collected byvacuum filtration to afford2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

Anhydrous DMF (5.0 mL) was added to a flask charged with2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(0.204 g, 0.894 mmol), sodium azide (0.070 g, 1.07 mmol), and ammoniumchloride (0.057 g, 1.07 mmol). The reaction was capped under nitrogenand heated to 120° C. After 48 h, the reaction was cooled to roomtemperature and concentrated in vacuo. The residue was purified onreverse phase HPLC (acetonitrile: water 0.1% TFA, 20-60% gradient). Thefractions containing product were collected and concentrated to one halfvolume and poured into saturated NaHCO₃ (50 mL). The aqueous phase waswashed trice with ethyl acetate (50 mL) and dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was triturated with methylenechloride and ethyl acetate to afford2-amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(14 mg, 6% yield) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d₆): δ8.55 (bs, 1H), 8.41 (bs, 1H), 7.32 (bs, 2H), 4.37 (q, J=7.2 Hz, 2H),2.60 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) for C₁₂H₁₃N₇O: 272.0(MH⁺).

Example 122-Amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

Potassium carbonate (0.539 g, 3.90 mmol) was added to a suspension of4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (0.413g, 1.95 mmol) from above, and malononitrile (0.194 g, 2.93 mmol) inabsolute ethanol (15.0 mL) and heated to 70° C. After one h, thereaction was allowed to cool to room temperature and concentrated invacuo. The residue was diluted with ethyl acetate (50 mL) and washedwith saturated NaHCO₃ (50 mL), and brine. The organic phase wasseparated and concentrated in vacuo. The residue was precipitated withethyl acetate and hexanes to give8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrileas a brown solid that was used in the subsequent step without furtherpurification.

Acetic anhydride (10.0 mL) was added to a flask charged with8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile(0.506 g, 1.95 mmol) and heated to 100° C. After one h, the reaction wasallowed to cool to room temperature and concentrated in vacuo. Theacetylated residue was then treated with 6 N HCl (40 mL) and heated to95° C. for one hour then transferred to a large flask. A saturatedsolution of NaHCO₃ (500 mL) was added slowly at 0° C. until a pH 8.0 wasachieved. The aqueous phase was washed thrice with ethyl acetate (100mL) and the organic layers combined, then washed with brine and driedover Na₂SO₄. The drying agent was filtered and concentrated in vacuo toafford crude8-ethyl-4-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrilewhich was used in the subsequent step without further purification.

3-Chloroperbenzoic acid (1.00 g, 5.85 mmol) was added to a solution ofcrude8-ethyl-4-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile(0.507 g, 1.95 mmol) in dichloromethane (30.0 mL) at room temperature.After 2.5 hours, the reaction was diluted with dichloromethane (50 mL)and washed twice with saturated NaHCO₃, followed by brine. The organicphase was separated and dried over Na₂SO₄, filtered, and concentrated invacuo.2-Amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrilewas used in the subsequent step without further purification.

Ammonium hydroxide (500 μL) was added to a solution of the above sulfonein dioxane (10 mL) at 0° C. The reaction flask sealed, and allowed towarm to room temperature upon standing overnight. The reaction wasconcentrated in vacuo triturated with ethyl acetate to afford theproduct which was used in the subsequent step without furtherpurification.

Tributyltin azide (660 μL, 2.41 mmol) was added to a flask charged with2-amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile(0.184 g, 0.803 mmol) in anhydrous toluene (5.0 mL). The reaction wasfitted with a reflux condenser and heated to 140° C. under a nitrogenatmosphere. After 20 h, the reaction was cooled to room temperature andthe precipitate collected by vacuum filtration and washed with absoluteethanol to give2-amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one(98 mg, 45% yield) as a light brown solid: ¹H NMR (400 MHz, 20% DCl inD₂O): δ 6.97 (s, 1H), 2.42 (q, J=7.2 Hz, 2H), 0.953 (s, 3H), −0.73 (t,J=7.2 Hz, 3H); MS (EI) for C₁₁H₁₁N₈O: 271.0 (MH⁺).

Example 13

A mixture of8-(3-methoxypropyl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(0.36 g, 1.29 mmol), prepared using procedures similar to thosedescribed in Example 1, dichloromethane (10 mL), and 77%3-chloroperbenzoic acid with water (0.723 g, 3.23 mmol) was stirred for1 h. The mixture was diluted with dichloromethane, washed with sat.sodium bicarbonate (3 times), brine, dried over sodium sulfate, and DCMwas removed under reduced pressure. The crude8-(3-methoxypropyl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-onewas used without further purification for subsequent step.

8-(3-methoxypropyl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one,and a solution of 2M ethylamine in THF (20 mL) was stirred for 2 h. THFwas removed under reduced pressure and the crude product was purified byflash column chromatography to give2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(0.18 g, 50% yield over 2 steps).

To a solution of2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one(0.18 g, 0.65 mmol), acetic acid (5 mL) and dichloromethane (3 mL) wasadded bromine (36 ul, 0.7 mmol). The mixture was stirred for 5 minutes,and then diluted with DCM and water. The organic layer was washed withsat. sodium bicarbonate (3 times), brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude product waspurified by flash column chromatography to gave 0.13 g (56% yield) of6-bromo-2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 5.44 (Br. s, 1H), 4.55 (m, 2H),3.54-3.47 (m, 4H), 3.33 (s, 3H), 2.53 (s, 3H), 2.05-2.00 (m, 2H),1.30-1.23 (m, 3H); MS (EI) for C₁₄H₁₉BrN₄O₂: 355 (MH+).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 13a

6-bromo-8-(2-ethoxyethyl)-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 5.37 (Br. s, 1H), 4.67 (m, 2H),3.74 (m, 2H), 3.61-3.56 (t, 2H), 3.51 (m, 2H), 2.53 (s, 3H), 1.29-1.25(t, 3H), 1.19-1.15 (t, 3H); MS (EI) for C₁₄H₁₉BrN₄O₂: 355 (MH+).

Example 13b

6-bromo-8-(3-ethoxypropyl)-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 5.37 (Br. s, 1H), 4.53 (m, 2H),3.52 (m, 4H), 3.48-3.43 (m, 2H), 2.53 (s, 3H), 2.04-2.00 (m, 2H),1.29-1.25 (t, 3H), 1.19-1.15 (t, 3H); MS (EI) for C₁₅H₂₁BrN₄O₂: 369(MH+).

Example 13c

6-bromo-2-(ethylamino)-8-(3-isopropoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 5.37 (Br. s, 1H), 4.53 (m, 2H),3.59-3.49 (m, 5H), 2.52 (s, 3H), 2.01-1.98 (m, 2H), 1.28-1.25 (t, 3H),1.13-1.11 (t, 6H); MS (EI) for C₁₆H₂₃BrN₄O₂: 383 (MH+).

Example 14

A mixture of 2,4-dichloro-6-methylpyrimidine (Aldrich, 5 g, 30 mmol),cyclohexylamine (3 g, 30 mmol) and DIEA (10 mL) was stirred at 80° C.for 12 h. The volatile material was removed under reduced pressure. Theresidue was loaded on a silica gel column, and was eluted withhexanes/ethyl acetate (3:1).8-cyclohexyl-2-(ethylamino)-4-methyl-6-(thiopheN-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-onewas obtained as colorless oil (2.8 g, 41% yield).

The product was reacted with a solution of ethylamine (10 equiv.) in THFat 100° C. for 12 h. The crude2-ethylamino-4-cyclohexylamino-6-methylpyrimidine was obtained from astandard workup and was used in the next step.

To a solution of 2-ethylamino-4-cyclohexylamino-6-methylpyrimidine (600mg, 2.56 mmol) in CH₃CN (10 mL) was added N-iodosuccinimide (NIS, 658mg, 2.92 mmol). The reaction was stirred for 2 h at room temperature.After removal of the solvent, the residue was dissolved in EtOAc. Theorganic phase was then washed with sodium bisulfite, brine, and driedover Na₂SO₄. Purification by flash column chromatography gave 660 mg(73% yield) of 2-ethylamino-4-cyclohexylamino-5-iodo-6-methylpyrimidine.

To a solution of2-ethylamino-4-cyclohexylamino-5-iodo-6-methylpyrimidine (660 mg, 1.83mmol) in DMA (7 mL) was added ethyl acrylate (458 mg, 4.58 mmol),Pd(OAc)₂ (121 mg, 0.18 mmol), (o-Tol)₃P (110 mg, 0.37 mmol), and Et₃N(740 mg, 7.32 mmol). The mixture was then stirred at 100° C. for 12 hunder N₂. Standard workup and purification by column chromatography gave411 mg (67% yield) of (E)-ethyl3-(4-(cyclohexylamino)-2-(ethylamino)-6-methylpyrimidin-5-yl)acrylate

(E)-ethyl3-(4-(cyclohexylamino)-2-(ethylamino)-6-methylpyrimidin-5-yl)acrylate(200 mg, 0.6 mmol) was dissolved in AcOH (2 mL). This solution washeated in a sealed tube at 186° C. for 17 h. Standard workup andpurification by column chromatography gave 65 mg (38% yield) of8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

To 8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-onein AcOH and CH₂Cl₂ was added Br₂ (22 uL, 0.42 mmol) at 80° C. Standardworkup and purification by column chromatography gave 65 mg (0.17 mmol,80% yield) of6-bromo-8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

The bromide (65 mg, 0.17 mmol) obtained above was reacted with2-thiopheneboronic acid (45 mg, 0.36 mmol) in the presence of Pd(PPh₃)₄(20 mg, 0.018 mmol) and Na₂CO₃ (38 mg, 0.36 mmol) in 1,4-dioxane/H2O(1:1) at 100° C. for 2 h. Removal of solvents and purification by columnchromatography gave 33 mg (50% yield) of8-cyclohexyl-2-(ethylamino)-4-methyl-6-(thiopheN-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one.¹H NMR (400 MHz, DMSO-d6)

8.01 (br s, 1H), 7.60 (m, 1H), 7.37 (m, 1H), 7.10 (m, 1H), 5.60-5.40 (m,1H), 3.55 (m, 2H), 2.85 (m, 1H), 2.61 (s, 3H), 1.90 (m, 2H), 1.71 (m,4H), 1.43 (m, 2H), 1.30-1.2 (m, 2H), 1.30 (t, 3H); MS (EI) forC₂₀H₂₄N₄OS: 369 (MH+).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compound was prepared:

Example 14a

6-bromo-8-cyclopropyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃)

8.06 (s, 1H), 5.37 (br s, 1H), 3.54 (m, 2H), 2.94 (br s, 1H), 2.51 (s,3H), 1.31-1.25 (m, 5H), 0.91 (br s, 2H); MS (EI) for C₁₃H₁₅BrN₄O: 323(MH+).

Example 15

To a solution of6-bromo-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg,0.35 mmol) in DMF (2 mL), prepared using procedures analogous to thosedescribed in Example 14, was added NaH (30 mg, 60%, 0.7 mmol). Themixture was stirred for 30 min at room temperature and was warmed to 70°C. 3-Bromopropanol (48 mg, 0.35 mmol) was then added. The stirring wascontinued for 12 h. Standard workup and purification by columnchromatography gave 33 mg (27% yield) of6-bromo-2-(ethylamino)-8-(3-hydroxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.¹H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 5.42 (br s, 1H), 4.59 (br s,2H), 3.50-3.47 (m, 5H), 2.55 (s, 3H), 2.02 (br s, 2H), 1.28 (t, 3H); MS(EI) for C₁₃H₁₇BrN₄O₂: 341 (MH+).

Using the same or analogous synthetic techniques and substituting withappropriate reagents, the following compounds were prepared:

Example 15a

6-bromo-2-(ethylamino)-8-(2-hydroxyethyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 4.82 (br s, 1H), 4.40 (br s,2H), 3.62-3.55 (m, 2H), 3.40-3.20 (m, 3H), 2.55 (s, 3H), 1.15 (t, 3H);MS (EI) for C₁₂H₁₅BrN₄O₂: 327 (MH⁺).

Example 15b

6-bromo-2-(ethylamino)-4-methyl-8-(2-(piperidin-1-yl)ethyl)pyrido[2,3-d]pyrimidin-7(8H)-one:¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 5.39 (br s, 1H), 4.59 (br s,2H), 3.55-3.40 (m, 2H), 2.70-2.50 (m, 6H), 2.52 (s, 3H), 1.62-1.58 (m,4H), 1.46-1.40 (m, 2H), 1.27 (t, 3H); MS (EI) for C₁₇H₂₄BrN₅O: 394(MH+).

BIOLOGICAL EXAMPLES Biological Example 1 PI3Kalpha Luciferase-CoupledChemiluminescence Assay Protocol

PI3Kα activity is measured as the percent of ATP consumed following thekinase reaction using luciferase-luciferiN-coupled chemiluminescence.Reactions were conducted in 384-well white, medium binding microtiterplates (Greiner). Kinase reactions were initiated by combining testcompounds, ATP, substrate (PIP2), and kinase in a 20 μL volume in abuffer solution. The standard PI3Kalpha assay buffer is composed 50 mMTris, pH 7.5, 1 mM EGTA, 10 mM MgCl₂, 1 mM DTT and 0.03% CHAPS. Thestandard assay concentrations for enzyme, ATP, and substrate are 0.5-1.1nM, 1 μM, and 7.5 μM, respectively. The reaction mixture was incubatedat ambient temperature for approximately 2 h. Following the kinasereaction, a 10 μL aliquot of luciferase-luciferin mix (PromegaKinase-Glo) was added and the chemiluminescence signal measured using aVictor2 plate reader (Perkin Elmer). Total ATP consumption was limitedto 40-60% and IC50 values of control compounds correlate well withliterature references.

Certain compounds of the invention were tested in this assay anddemonstrated the ability to bind to PI3K. For example, in one embodimentof the invention, the PI3K inhibitor is selected from the compounds inTable 1 having a PI3K-binding affinity of about 9 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 5 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 3 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 1.5 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 1 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.6 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.3 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.2 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.1 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.04 μM or less. In anotherembodiment, the PI3K inhibitor is selected from the compounds in Table 1having a PI3K-binding affinity of about 0.020 μM or less.

Biological Example 2

Phospho AKT assay PC-3 cells were seeded on 6-well plates at 150,000cells/well. Cells were cultured for 3 days, then treated with compoundsin serum-free medium for 3 hr. EGF (100 ng/mL) was added for the last 10min. Cells were lysed in TENN buffer. Phospho T308 Akt and total Aktwere quantified by ELISA performed according to the Biosource assayprotocol. The readings of phospho Akt were normalized to total Aktreadings.

Biological Example 3 Phospho S6 Assay

PC-3 cells were seeded on 96-well plates at 8,000 cells/well. For eachexperiment, cells were seeded and treated in duplicated plates: oneplate for phospho S6 CellELISA, and one plate for total S6 CellELISA.Cells were cultured on the plates for 3 days, then treated withcompounds in serum-free medium for 3 hr in triplicate. Cells were fixedwith 4% formaldehyde, quenched with 0.6% H₂O₂, blocked with 5% BSA,incubated with either phospho S6 antibody or total S6 antibodyovernight, incubated with goat-anti-rabbit-IgG-HRP for 1 hr, anddeveloped in chemiluminescent substrate.

Biological Example 4 PIP₃ Assay

MCF-7 cells grown in 10-cm dishes were starved for 3 hours in DMEM, andthen treated with compounds for 20 minutes. In the last 2 minutes of theincubation with the compounds, EGF (100 ng/mL) was added to stimulatethe production of PIP3. The medium was aspirated and the cells werescraped with 10% trichloroacetic acid. The lipids were extracted fromthe pellet after the cell lysates were centrifuged. PIP3 in the cellularlipid extraction was quantified with the AlphaScreen assay in whichGrp1-PH is used as the PIP3 specific probe. The amount of cellular PIP3was calculated from the standard curve of diC₈ PI (3,4,5) P3.

Biological Example 5-10 In Vivo Models

Compound A is a Compound of Formula I. Compound B isN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.

Female and male athymic nude mice (NCr) 5-8 weeks of age and weighingapproximately 20-25 g were used in the following model. Prior toinitiation of a study, the animals were allowed to acclimate for aminimum of 48 h. During these studies, animals were provided food andwater ad libitum and housed in a room conditioned at 70-75° F. and 60%relative humidity. A 12 h light and 12 h dark cycle was maintained withautomatic timers. All animals were examined daily for compound-inducedor tumor-related deaths.

PC-3 human prostate adenocarcinoma cells were cultured in vitro in DMEM(Mediatech) supplemented with 20% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization and 3×10⁶ cells (passage 13, 99% viability) in 0.1 mL ofice-cold Hank's balanced salt solution were implanted subcutaneouslyinto the hindflank of 5-8 week old male nude mice. A transponder wasimplanted in each mouse for identification, and animals were monitoreddaily for clinical symptoms and survival. Body weights were recordeddaily. Experiments were conducted with Compound A as a single agent aswell as Compound A in combination with Taxol and Compound A incombination with Rapamycin. This model can be used to assess thedesirability of treating with Compound A in combination with otheranti-cancer agents.

U-87 MG human glioblastoma cells were cultured in vitro in DMEM(Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone),PenicilliN-Streptomycin and non-essential amino acids at 37° C. in ahumidified 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization and 2×10⁶ cells (passage 5, 96% viability) in 0.1 mL ofice-cold Hank's balanced salt solution were implanted intradermally intothe hindflank of 5-8 week old female nude mice. A transponder wasimplanted in each mouse for identification, and animals were monitoreddaily for clinical symptoms and survival. Body weights were recordeddaily. Experiments were conducted with Compound A as a single agent andthe results are not included. This model can be used to assess thedesirability of treating with Compound A in combination with otheranti-cancer agents.

A549 human lung carcinoma cells were cultured in vitro in DMEM(Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone),PenicilliN-Streptomycin and non-essential amino acids at 37° C. in ahumidified 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization and 10×10⁶ cells (passage 12, 99% viability) in 0.1 mL ofice-cold Hank's balanced salt solution were implanted intradermally intothe hindflank of 5-8 week old female nude mice. A transponder wasimplanted in each mouse for identification, and animals were monitoreddaily for clinical symptoms and survival. Body weights were recordeddaily. Experiments were conducted with Compound A as a single agent aswell as Compound A in combination with Compound B. This model can beused to assess the desirability of treating with Compound A incombination with other anti-cancer agents.

MDA-MB-468 human breast adenocarcinoma cells, passage number <6, weremaintained and propagated in log-phase growth in Dulbecco's Modificationof Eagles's Medium (DMEM; Mediatech) containing L-Glutamine supplementedwith 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin andnon-essential amino acids at 37° C. in a humidified, 5% CO₂ atmosphere.On day 0, cells were harvested by trypsinization, and 10×10⁶ cells(passage 10, 98% viability) in 50% cold Hanks balanced salt solution/50%Matrigel (100 μL total volume per mouse) were implanted subcutaneouslyinto the mammary fat pads of female nude mice. Experiments wereconducted with Compound A as a single agent as well as Compound A incombination with erlotinib. This model can be used to assess thedesirability of treating with Compound A in combination with otheranti-cancer agents.

Calu-6 human lung anaplastic carcinoma cells were cultured in vitro inDMEM

(Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified, 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization, and 5×10⁶ cells (passage #8, 96% viability) in 0.1 mLice-cold Hank's balanced salt solution were implanted intradermally inthe hind-flank of 5-8 week old female athymic nude mice. A transponderwas implanted in each mouse for identification, and animals weremonitored daily for clinical symptoms and survival. Body weights wererecorded daily. Experiments were conducted with Compound A as a singleagent as well as Compound A in combination with carboplatin. This modelcan be used to assess the desirability of treating with Compound A incombination with other anti-cancer agents.

MCF7 human mammary adenocarcinoma cells were cultured in vitro in DMEM(Cellgro) supplemented with 10% Fetal Bovine Serum (Cellgro),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization, and 5×10⁶ cells (passage 10 and 95% viability for Study1, passage 9 and 90% viability for Study 2) in 100 μL of a solution madeof 50% cold Hanks balanced salt solution with 50% growth factor reducedmatrigel (R&D Systems for Study 1 and Becton Dickinson for Study 2)implanted subcutaneously into the hindflank of female nude mice. Atransponder was implanted into each mouse for identification and datatracking, and animals were monitored daily for clinical symptoms andsurvival. During the dosing period, the tumor weight of each animal wasdetermined twice weekly and the body weight of each animal was measureddaily. Experiments were conducted with Compound A as a single agent aswell as Compound A in combination with Compound B. This model can beused to assess the desirability of treating with Compound A incombination with other anti-cancer agents.

For subcutaneous or intradermal tumors, the mean tumor weight of eachanimal in the respective control and treatment groups was determinedtwice weekly during the study. Tumor weight (TW) was determined bymeasuring perpendicular diameters with a caliper, using the followingformula:

tumor weight (mg)=[tumor volume=length (mm)×width² (mm²)]/2

These data were recorded and plotted on a tumor weight vs. dayspost-implantation line graph and presented graphically as an indicationof tumor growth rates. Percent inhibition of tumor growth (TGI) isdetermined with the following formula:

$( {1 - ( \frac{( {X_{f} - X_{0}} )}{( {Y_{f} - X_{0}} )} )} )*100$

-   -   where X₀=average TW of all tumors on group day    -   X_(f)=TW of treated group on Day f    -   Y_(f)=TW of vehicle control group on Day f        If tumors regress below their starting sizes, then the percent        tumor regression is determined with the following formula:

$( \frac{( {X_{0} - X_{f}} )}{X_{0}} )*100$

Tumor size is calculated individually for each tumor to obtain amean±SEM value for each experimental group. Statistical significance isdetermined using the 2-tailed Student's t-test (significance defined asP<0.05).

Biological Examples 11-14

Compound A is a Compound of Formula I and is an inhibitor of class IPI3-kinases. Compound B isN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.

Prostate Cancer Xenograft Model A Compound of Formula I in Combinationwith Taxol

Compound A was tested alone and in combination with taxol in a prostatecarcinoma tumor model. PC-3 is a human prostate carcinoma cell line thatharbors a homozygous deletion mutation in PTEN, which results inconstitutive activation of the PI3K pathway. In single-dosepharmacodynamic experiments, oral administration of Compound A resultedin a dose-dependent decrease in the phosphorylation of AKT, p70S6K, andS6 in PC-3 tumors grown ectopically in mice. Repeat-dose administrationof Compound A also inhibited the growth of these tumors, but did notinduce regressions.

Oral administration of Compound A at 100 mg/kg q2d or 30 mg/kg bidresulted in substantial tumor growth inhibition. See FIG. 1. Comparabletumor growth inhibition was achieved with 7.5 mg/kg taxol administeredi.v. twice weekly. While tumor growth was inhibited substantially withCompound A alone, the combination of either dose of Compound A withtaxol was superior to either agent alone and induced significantregression of the tumors. Body weight loss and dose skipping was minimalin all groups, and was not exacerbated in the combination groupindicating that the combination was well tolerated. These resultssupport the use of a Compound of Formula I in combination with taxol intumors with constitutively activated PI3K signaling.

Prostate Cancer Xenograft Model A Compound of Formula I in Combinationwith Rapamycin

Compound A was tested alone and in combination with rapamycin in aprostate carcinoma tumor model (PC-3 cell line). Oral administration ofCompound A at 100 mg/kg q2d resulted in significant tumor growthinhibition. See FIG. 2. Significant tumor growth inhibition was alsoobserved with 5 mg/kg rapamycin administered i.p. daily. While tumorgrowth was inhibited substantially with Compound A alone, thecombination of Compound A with rapamycin was transiently superior toeither agent alone and induced regression of the tumors, although thefinal tumor weights were similar between rapamycin alone and thecombination treatment. Body weight loss and dose skipping was minimalwith each agent alone, but body weight loss was exacerbated in thecombination group necessitating dose skipping. The fact that tumorregression was observed despite dose skipping suggests that using anintermittent dosing schedule would maintain efficacy and improvetolerability.

At the end of the efficacy study, tumors were resected and processed forhistological analysis of markers of proliferation (Ki67) and apoptosis(TUNEL). Administration of Compound A as monotherapy (100 mg/kg q2d) wasassociated with a significant 44% decrease in the fraction ofproliferating cells. Administration of rapamycin as monotherapy was alsoassociated with a decrease (77%) in the fraction of proliferating cells.Combined administration of Compound A and rapamycin resulted in a stronganti-proliferative effect (96% decrease) which was significantlyenhanced over that seen with monotherapy (FIG. 6). Administration ofCompound A as monotherapy was associated with a significant 3.6-foldinduction in the fraction of apoptotic cells, whereas rapamycinadministered as monotherapy did not exert significant pro-apoptoticeffects. Combined administration of Compound A and rapamycin resulted ina 7-fold induction in the fraction of apoptotic cells, which wassignificantly enhanced over that seen with monotherapy (FIG. 7).Together, these data indicate that coadministration of Compound A andrapamycin leads to a significant decrease in tumor cell proliferationand a significant increase in tumor cell apoptosis compared to eitheragent administered as monotherapy. These results support the use of aCompound of Formula I in combination with rapamycin in tumors withconstitutively activated PI3K signaling.

Non-Small Cell Lung Cancer Xenograft Model A Compound of Formula I inCombination with Carboplatin

Compound A was tested both as a single agent and in combination withcarboplatin in a NSCLC tumor model. Calu-6 is a human NSCLC cell linethat harbors a heterozygous activating mutation in K-Ras (Q61K).

Oral administration of Compound A at 100 mg/kg q2d or 30 mg/kg bid tomice bearing Calu-6 tumors resulted in substantial tumor growthinhibition. See FIG. 3. Both dose schedules resulted in similarinhibition of tumor growth. Significant tumor growth inhibition was alsoobserved with 50 mg/kg carboplatin administered i.v. q4d, but was not aspronounced as with Compound A. The combination of Compound A 100 mg/kgq2d and carboplatin was superior to either agent alone, however, thecombination of Compound A 30 mg/kg bid with carboplatin was notsignificantly different from Compound A 30 mg/kg bid alone. Body weightloss and dose skipping was minimal in all groups, and was notexacerbated in the combination group indicating that the combination waswell tolerated. These results support the use of a Compound of Formula Iin combination with platins in tumors with activating mutations inK-Ras.

Non-Small Cell Lung Cancer Xenograft Model A Compound of Formula I inCombination with Compound B

Compound A was tested both as a single agent and in combination withCompound B, an EGFR inhibitor, in a NSCLC tumor model. The A549 humannon-small cell lung carcinoma cell line harbors a homozygous stopmutation in the gene encoding LKB1, and an activating G12S mutation inK-Ras, promoting activation of both PI3K and mTOR. A549 cells alsoexpress wild-type EGFR.

Oral single-agent administration of Compound B at 30 mg/kg qd for 18days caused a significant tumor growth inhibition of 80%. See FIG. 4 a.Compound A administered qd as a single agent at 30 mg/kg caused asignificant tumor growth inhibition of 80%. Oral administration ofCompound B at 30 mg/kg qd followed by administration of Compound A at 30mg/kg qd after about six hours led to a significant TGI of 93%, whichtrended towards an increased anti-tumor efficacy compared to theefficacy of the single treatments, although this did not reachstatistical significance in these studies. One possible explanation forthe modest effect of the combination is the short duration of the dosingperiod (14 days), which may be too short to observe the full benefit ofthe combination. Longer dosing regimes may produce more significantdifferences, as the anticipated effect of dual inhibition of PI3K/mTORand EGFR on cell growth and survival becomes more apparent.

As a single agent Compound B dosed at 30 mg/kg qd was generally welltolerated, with a body weight loss of 1.5 to 7% with no dose omission.Compound A dosed at 30 mg/kg qd was also well tolerated with no doseskipping and non-significant body weight loss. Co-administration ofCompound B at 30 mg/kg qd with Compound A at 30 mg/kg qd was associatedwith a body weight loss of 3 to 12%, which was necessitated minimal doseskipping (2 doses) with no dose skipping for the last 8 days.

Breast Cancer Xenograft Model A Compound of Formula I in Combinationwith Compound B

Compound A, a PI3K inhibitor, was tested both as a single agent and incombination with Compound B, an EGFR inhibitor, in a breast cancer tumormodel. The MCF7 human mammary adenocarcinoma cell line harbors aheterozygous, activating mutation in PI3K (PI3KCA/E545K) and expresseswild-type EGFR.

Compound B was administered orally once-daily (qd) at 30 mg/kg, andCompound A was orally administered once-daily at 30 mg/kg. Combinationtherapies consisted of administering Compound B at 30 mg/kg qd followedby administration of Compound A at 30 mg/kg qd within about 6-7 hours.Single agent administration of Compound B at 30 mg/kg qd for 14 dayscaused a tumor growth inhibition of 38 to 61%. See FIGS. 4 b-1 and 4b-2. Tumor growth inhibition of 53-76% was observed with Compound Adosed at 30 mg/kg qd. The combination of Compound B dosed at 30 mg/kg qdwith Compound A dosed at 30 mg/kg qd resulted in significant tumorgrowth inhibition of 83-87%, which trended towards an increasedanti-tumor efficacy compared to the efficacy of the single treatments,although this did not reach statistical significance in these studies.One possible explanation for the modest effect of the combination is theshort duration of the dosing period (14 days), which may be too short toobserve the full benefit of the combination. Longer dosing regimes mayproduce more significant differences, as the anticipated effect of dualinhibition of PI3K and EGFR on cell growth and survival becomes moreapparent. In both studies (FIGS. 4 b-1 and 4 b-2) the average tumor sizein the combination groups is still decreasing at the last measurementpoint.

At the end of the study, tumors were resected and processed for analysisof proliferating cells (Ki67 staining), determination of microvesseldensity (MVD) following immunostaining for CD31, and for TUNEL(apoptotic cells) analysis (see Tables 8 and 9). Administration ofCompound B dosed at 30 mg/kg qd caused a significant 14 to 19% decreasein the number of viable, Ki67-positive proliferating tumor cells whencompared to the vehicle control-treated group. Compound A dosed at 30mg/kg qd did cause a significant 13% decrease in Ki67-positive cellsonly in Study 2. Combination of Compound B with Compound A caused asignificant 23 to 37% decrease in Ki67 positive tumor cells, which wassignificantly more efficacious in this model than the single agenttreatments (however not better than Compound B single arm in Study 1).Treatment with Compound B dosed at 30 mg/kg qd did not result in asignificant induction of TUNEL-positive (apoptotic) cells compared tothe vehicle control-treated group. Administration of Compound A dosed at30 mg/kg qd did not cause a significant induction of apoptotic tumorcells. Combining Compound B with Compound A did not result in asignificant induction of apoptosis compared to vehicle control.Administration of Compound B dosed at 30 mg/kg qd and Compound A dosedat 30 mg/kg qd caused a significant 31% and 32% decrease, respectively,in CD31-positive tumor vessels. The combination of Compound B withCompound A caused a 22% decrease in MVD, which was not significantlydifferent from Compound B or Compound A single agent treatment.End-of-study immunohistochemical analyses suggest that co-administrationof Compound B and Compound A may provide an additional benefit on theanti proliferative, but not the anti-angiogenic effect of the singleagents in MCF-7 tumors.

As a single agent Compound B dosed at 30 mg/kg qd was generally welltolerated, with a final body weight loss of 4.5 to 6.1% (notsignificantly different from the vehicle-treated control group) and 7 to13 dose omissions. The majority of the skipped doses (11 out of 13) inStudy 1 came from one mouse maintaining a low body weight throughout thestudy from dose day 3. Administration of Compound A dosed at 30 mg/kg qdwas also well tolerated with 3 to 9 doses skipped and non-significantbody weight loss or gain. Co-administration of Compound B at 30 mg/kg qdwith Compound A at 30 mg/kg qd was associated with a body weight loss of0.3 to 10% throughout the study and minimal dose skipping (6 to 11doses). By the end of the dosing period there was a non-significant lossof 0.3 to 6.2% in body weight.

Breast Cancer Xenograft Model A Compound of Formula I in Combinationwith Erlotinib

Compound A was tested both as a single agent and in combination witherlotinib, in an erolitinib-resistant tumor model with elevated PI3Ksignaling. MDA-MB-468 is a human breast carcinoma cell line that has anincrease in the copy number of the EGFR gene and a homozygous deletionof PTEN. In vitro treatment of these cells with EGFR inhibitors such aserlotinib inhibits EGFR activity but fails to downregulate the PI3Kpathway.

Oral administration of erlotinib at 100 mg/kg qd to mice bearingMDA-MB-468 tumors resulted in significant but incomplete tumor growthinhibition. See FIG. 5. Oral administration of Compound A at 100 mg/kgq2d also resulted in tumor growth inhibition. The combination of the twoagents was modestly superior to either agent alone. The relativelymodest increase in efficacy in the combination group could improve withaltering the dose and schedule for the administration of Compound A.

Mice administered Compound A at 100 mg/kg q2d exhibited a rate of bodyweight gain comparable to vehicle controls. Mice administered erlotinibexhibited an apparent decrease in their rate of body weight gainrelative to vehicle controls. Coadministration with erlotinib resultedin a loss in body weight in mice treated with Compound A (10% bodyweight loss from start of dosing). Consistent with these data, onlyminimal dose-skipping was required when Compound A was administered asmonotherapy (1-3 doses skipped), but substantial dose-skipping wasrequired for Compound A when erlotinib was coadministered. These resultssupport the use of a Compound of Formula I in combination with erlotinibin tumors expressing EGF receptors and harboring PTEN deletions.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specificembodiments and techniques. However, it should be understood that manyvariations and modifications may be made while remaining within thespirit and scope of the invention. It will be obvious to one of skill inthe art that changes and modifications may be practiced within the scopeof the appended claims. Therefore, it is to be understood that the abovedescription is intended to be illustrative and not restrictive. Thescope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the following appended claims, along with the fullscope of equivalents to which such claims are entitled. All patents,patent applications and publications cited in this application arehereby incorporated by reference in their entirety for all purposes tothe same extent as if each individual patent, patent application orpublication were so individually denoted.

1. A method of treating cancer which method comprises administering to apatient a therapeutically effective amount of a Compound of Formula I:

or a single isomer thereof where the compound is optionally as apharmaceutically acceptable salt and additionally optionally as ahydrate and additionally optionally as a solvate thereof, oradministering to a patient a pharmaceutical composition comprising atherapeutically effective amount of a Compound of Formula I and apharmaceutically acceptable carrier, excipient, or diluent; incombination with one or more treatments independently selected fromsurgery, one or more chemotherapeutic agents, one or more of the hormonetherapies, one or more antibodies, one or more immunotherapies,radioactive iodine therapy, and radiation wherein the Compound ofFormula I is that wherein: R¹ is hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heterocycloalkyl, optionallysubstituted heterocycloalkylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; R² is hydrogen or alkyl wherethe alkyl is optionally substituted with 1, 2, 3, 4, or 5 R⁸ groups; Xis —NR³—; R³ hydrogen; R⁴ is optionally substituted alkyl; R⁵ ishydrogen; and R⁶ is phenyl, acyl, or heteroaryl wherein the phenyl andheteroaryl are optionally substituted with 1, 2, 3, 4, or 5 R⁹ groups;each R⁸, when present, is independently hydroxy, halo, alkoxy,haloalkoxy, amino, alkylamino, dialkylaminoalkyl, or alkoxyalkylamino;and each R⁹, when present, is independently halo, alkyl, haloalkyl,alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkoxyalkyl,carboxyalkyl, alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl, arylalkyl,aryloxy, heterocycloalkyl, or heteroaryl and where the cycloalkyl, aryl,heterocycloalkyl, and heteroaryl, each either alone or as part ofanother group within R⁹, are independently optionally substituted with1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy,alkoxy, haloalkoxy, amino, alkylamino, and dialkylamino.
 2. The methodof claim 1 where the cancer is selected from breast cancer, coloncancer, rectal cancer, endometrial cancer, gastrointestinal carcinoidtumors, gastrointestinal stromal tumors, glioblastoma, hepatocellularcarcinoma, small cell lung cancer, non-small cell lung cancer, melanoma,ovarian cancer, cervical cancer, pancreatic cancer, prostate carcinoma,acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin'slymphoma, and thyroid carcinoma. 3-6. (canceled)
 7. The method of claim1 where the treatment is one chemotherapeutic agent and thechemotherapeutic agent is a platin.
 8. The method of claim 1 where thetreatment is one chemotherapeutic agent and the chemotherapeutic agentis a taxane.
 9. The method of claim 1 where the treatment is onechemotherapeutic agent and the chemotherapeutic agent is rapamycin or arapamycin analogue. 10-16. (canceled)
 17. The method of claim 1 wherethe Compound of Formula I is selected from:8-ethyl-2-(ethylamino)-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;6-biphenyl-4-yl-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-(2,4-difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-(3-chloro-4-fluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[4-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;6-(2,4-dichlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-(3,4-difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[2-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[4-(phenyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;6-[2,4-bis(methyloxy)phenyl]-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[3-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[3-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;6-(3-chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-(4-chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;1,1-dimethylethyl2-[8-ethyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl]-1H-pyrrole-1-carboxylate8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-(5-chloro-2-thienyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(3-fluoropyridiN-4-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[1-(phenylmethyl)-1H-pyrazol-4-yl]pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(1H-indol-6-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(5-phenyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-6-furan-3-yl-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclohexyl-2-(ethylamino)-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-(methylamino)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-cyclopentyl-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-[(2-fluoroethyl)amino]-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-4-methyl-8-(phenylmethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-[4-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-(4-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-(3-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-6-isoxazol-4-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-6-furan-2-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-6-(2,4-dichlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;5-(2-amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)thiophene-2-carbonitrile2-amino-8-ethyl-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-6-(1H-imidazol-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-4,8-diethyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;and2-amino-8-cyclopentyl-4-methyl-6-(1,3-thiazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;

where the Compound is optionally as a pharmaceutically acceptable saltand additionally optionally as a hydrate and additionally optionally asa solvate thereof.
 18. The method of claims 1, 2, or 17 where thetreatment is one antibody selected from an EGFR antibody and an ErbB2antibody, or the treatment is one or two chemotherapeutic agentsindependently selected from rapamycin, a rapamycin analogue, analkylating agent a taxane, a platin, an EGFR inhibitor, and an ErbB2inhibitor.
 19. The method of claim 18 where the treatment is one or twochemotherapeutic agents independently selected from rapamycin,paclitaxel, carboplatin, lapatinib, and erlotinib.
 20. (canceled) 21.The method of claim 1, 2, or 17 where the treatment is onechemotherapeutic agent where the chemotherapeutic agent is erlotinib.22. The method of claim 1, 2, or 17 where the treatment is onechemotherapeutic agent where the chemotherapeutic agent is lapatinib.23. The method of claim 1, 2, or 17 where the treatment is onechemotherapeutic agent where the chemotherapeutic agent is carboplatin.24. The method of claim 1, 2, or 17 where the treatment is onechemotherapeutic agent where the chemotherapeutic agent is paclitaxel.25. The method of claim 1, 2, or 17 where the treatment is onechemotherapeutic agent where the chemotherapeutic agent is rapamycin.26. The method of claim 1, 2, or 17 where the treatment is one antibodyselected from bevacizumab, trastuzumab, cetuximab, and panitumumab. 27.(canceled)
 28. The method of claim 1, 2, or 17 where the treatment isone chemotherapeutic agent and the chemotherapeutic agent istemozolomide.